Table 1. Open in new tab Summary of CDED...

Study	Study Population	Study Design	Intervention Group	Study Duration	Main Outcomes
Pediatric Studies
Sigall-Boneh 2014²²	Active CD patients from Israel, mostly mild to moderate disease. (n = 47; 13 were young adults)	Retrospective quasi-experiment	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks, or CDED alone	12 weeks	Clinical response and remission were achieved in 79% and 71%, respectively, at week 6. CRP was normalized in 70%
Sigall-Boneh 2017²³	CD patients with loss of response to biologics (n = 21; 11 were young adults)	Retrospective quasi-experiment	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks, or CDED alone. Severe patients started with EEN for 2 weeks and continued with CDED plus PEN	12 weeks	Clinical response and remission were achieved in 90% and 62%, respectively, and lead to improvement in inflammatory markers at week 6
Levine 2019¹⁴	Mild to moderate luminal CD patients from Israel and Canada (n = 78)	RCT	Group1: CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks; Group2: EEN for 6 weeks followed by a free diet with 25% PEN for another 6 weeks	12 weeks	CDED plus PEN was better tolerated than EEN and led to 75% clinical remission vs 59% in the EEN group at week 6; CDED + PEN was superior to EEN group at 12 weeks in all clinical parameters
Sigall-Boneh 2021²⁴	The same RCT¹⁴ cohort	Post hoc analysis	2 interventional groups as describe previously	12 weeks	Both groups (CDED and EEN) induced rapid responses (82% and 85% respectively) at week 3
Levine 2020²⁵	Active CD from Israel (n = 4)	Case Series	CDED plus PEN	Up to 3 years	Case 1 and 2: CDED plus PEN effective monotherapy in uncomplicated mild-moderate CD disease, with > 1 year sustained remission recorded. Case 3: In penetrating disease, CDED plus PEN effective as a combination maintenance therapy post induction of remission with 8/52 EEN, antibiotics and anti-TNF. Resolution of fistula and perianal disease at 4 months repeat MRE. Case 4: CDED and PEN effective as rescue therapy in refractory patient. Regained response to biologics and sustained remission at 5 months.
Scarallo 2021²⁶	Mild to moderate luminal-colonic CD patients from Italy	Cases series	CDED plus PEN or CDED alone	Up to 52 weeks	CDED with or withoutPEN presented a safe and effective therapeutic option asboth induction and maintenance monotherapy
Niseteo 2021¹⁷	Active CD patients from Croatia (n = 61)	Retrospective comparative study	2 interventional groups: EEN and CDED plus PEN. In the CDED plus PEN group, 80% of patients initially received EEN for 1-2 weeks.	6-8 weeks	CDED + PEN resulted in a 75% remission rate and was as effective as EEN in inducing remission and improved weight gain.
Matuszczyk 2022¹⁶	Mild-moderate CD patients with elevated FCP (n = 48) from Poland	Prospective quasi-experiment	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks	12 weeks	FCP levels were normalized in 35%; 50% decrease in FCP in 54%
Stein 2022²⁷	Remission CD (age 13-23 years) in Israel and USA (n = 18)	Prospective comparative study	Diets following withdrawal of immunomodulator or anti-TNF Group 1: CDED plus PEN Group 2: Free diet	52 weeks	No significant difference in 52-week remission rates (5/9; 55.6%) amongst CDED vs Free diet group (5/7; 71.4%), P = .63.
Martín-Masot 2023²⁸	Mild- moderate CD (age 8-18 years) from Spain (n = 24)	Prospective to assess changes in dietary habits on CDED and compliance after 1 year	24 hour recall at baseline and 52 weeks on CDED	52 weeks	CDED resulted in reduction in the intake of ultra-processed foods (UPFs); a higher adherence to the Mediterranean diet (KIDMED score: 5 ± 2.1 at baseline vs 7.5 ± 1.4 at 52 weeks. After 52 weeks of CDED treatment, no patient had a very poor-quality diet compared with 33.33% at baseline.
María Clara Jijón Andrade 2023²⁹	New onset mild to moderate and loss of response to biologics (age 10.7-15) from Spain (n = 15)	Retrospective quasi-experiment	CDED + PEN	24 Weeks	CDED + PEN among 15 patients with CD resulted in remission in all patients at week 6 and 12. Among them, 87% of treatment naïve patients-maintained remission at week 24 compared with 67% in patients who lost response to biologics. In treatment naïve patients the FCP and albumin improved at week 6, week 12, and week 24 (P < .05). Whereas in patients who loss response to biologics the reduction in FCP did not reach a level of significant.
Adult Studies
Szczubelek 2021³⁰	Adults with mild—severe CD CDAI > 150 (n = 32) from Poland	Real world evidence	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks;	12 weeks	Clinical remission was obtained in 76.7% patients after 6 weeks and in 82.1% after 12 weeks of CDED. FCP improved vs baseline (P = .021).
Yanai 2022¹⁵	Adults (18-55 years) with mild—moderate CD (HBI 5-14) from Israel (n = 44)	Open-label, pilot randomised trial	Group 1: CDED plus partial enteral nutrition Group 2: CDED alone for 24 weeks.	24 weeks	At week 6, CDED + PEN resulted in 68% remission rate and CDED alone resulted in 57% clinical remission. 80% of those in remission at week 6 sustained remission at week 24.
Fliss Isakov 2023³¹	Adults (>18 years) with active pouchitis: cPDAI > 2 and mPDAI ≥ 5 (n = 8) from Israel	Nonrandomized, noncontrolled, open-label, Interventional Pilot Study	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks	12 weeks	Clinical remission (cPDAI subscore 2) was achieved by 66.7%, 60%, and 46.7% of patients at Weeks 6, 12, and 24, respectively.

Study

Study Population

Study Design

Intervention Group

Study Duration

Main Outcomes

Pediatric Studies

Sigall-Boneh 2014²²

Active CD patients from Israel, mostly mild to moderate disease. (n = 47; 13 were young adults)

Retrospective quasi-experiment

CDED plus 50% PEN for 6 weeks followed by CDED with
25% PEN for another 6 weeks, or CDED alone

12 weeks

Clinical response and remission were achieved in 79% and 71%, respectively, at week 6. CRP was normalized in 70%

Sigall-Boneh 2017²³

CD patients with loss of response to biologics (n = 21; 11 were young adults)

Retrospective quasi-experiment

CDED plus 50% PEN for 6 weeks followed by CDED with
25% PEN for another 6 weeks, or CDED alone.
Severe patients started with EEN for 2 weeks and continued with CDED plus PEN

12 weeks

Clinical response and remission were achieved in 90% and 62%, respectively, and lead to improvement in inflammatory markers at week 6

Levine 2019¹⁴

Mild to moderate luminal CD patients from Israel and Canada (n = 78)

RCT

Group1: CDED plus 50% PEN for 6 weeks followed by CDED with
25% PEN for another 6 weeks; Group2: EEN for 6 weeks followed by a free diet with 25% PEN for another 6 weeks

12 weeks

CDED plus PEN was better tolerated than EEN and led to 75% clinical remission vs 59% in the EEN group at week 6; CDED + PEN was superior to EEN group at 12 weeks in all clinical parameters

Sigall-Boneh 2021²⁴

The same RCT¹⁴ cohort

Post hoc analysis

2 interventional groups as describe previously

12 weeks

Both groups (CDED and EEN) induced rapid responses (82% and 85% respectively) at week 3

Levine 2020²⁵

Active CD from Israel
(n = 4)

Case Series

CDED plus PEN

Up to 3 years

Case 1 and 2: CDED plus PEN effective monotherapy in uncomplicated mild-moderate CD disease, with > 1 year sustained remission recorded.
Case 3: In penetrating disease, CDED plus PEN effective as a combination maintenance therapy post induction of remission with 8/52 EEN, antibiotics and anti-TNF. Resolution of fistula and perianal disease at 4 months repeat MRE.
Case 4: CDED and PEN effective as rescue therapy in refractory patient. Regained response to biologics and sustained remission at 5 months.

Scarallo 2021²⁶

Mild to moderate luminal-colonic CD patients from Italy

Cases series

CDED plus PEN or CDED alone

Up to 52 weeks

CDED with or withoutPEN presented a safe and effective therapeutic option asboth induction and maintenance monotherapy

Niseteo 2021¹⁷

Active CD patients from Croatia (n = 61)

Retrospective comparative study

2 interventional groups: EEN and CDED plus PEN. In the CDED plus PEN group, 80% of patients initially received EEN for 1-2 weeks.

6-8 weeks

CDED + PEN resulted in a 75% remission rate and was as effective as EEN in inducing remission and improved weight gain.

Matuszczyk 2022¹⁶

Mild-moderate CD patients with elevated FCP (n = 48) from Poland

Prospective quasi-experiment

CDED plus 50% PEN for 6 weeks followed by CDED with
25% PEN for another 6 weeks

12 weeks

FCP levels were normalized in 35%; 50% decrease in FCP in 54%

Stein 2022²⁷

Remission CD (age 13-23 years) in Israel and USA
(n = 18)

Prospective comparative study

Diets following withdrawal of immunomodulator or anti-TNF
Group 1: CDED plus PEN
Group 2: Free diet

52 weeks

No significant difference in 52-week remission rates (5/9; 55.6%) amongst CDED vs Free diet group (5/7; 71.4%), P = .63.

Martín-Masot 2023²⁸

Mild- moderate CD
(age 8-18 years) from Spain (n = 24)

Prospective to assess changes in dietary habits on CDED and compliance after 1 year

24 hour recall at baseline and 52 weeks on CDED

52 weeks

CDED resulted in reduction in the intake of ultra-processed foods (UPFs); a higher adherence to the Mediterranean diet (KIDMED score: 5 ± 2.1 at baseline vs 7.5 ± 1.4 at 52 weeks. After 52 weeks of CDED treatment, no patient had a very poor-quality diet compared with 33.33% at baseline.

María Clara Jijón Andrade 2023²⁹

New onset mild to moderate and loss of response to biologics (age 10.7-15) from Spain (n = 15)

Retrospective quasi-experiment

CDED + PEN

24 Weeks

CDED + PEN among 15 patients with CD resulted in remission in all patients at week 6 and 12. Among them, 87% of treatment naïve patients-maintained remission at week 24 compared with 67% in patients who lost response to biologics.
In treatment naïve patients the FCP and albumin improved at week 6, week 12, and week 24 (P < .05). Whereas in patients who loss response to biologics the reduction in FCP did not reach a level of significant.

Adult Studies

Szczubelek 2021³⁰

Adults with mild—severe CD CDAI > 150 (n = 32) from Poland

Real world evidence

CDED plus 50% PEN for 6 weeks followed by CDED with
25% PEN for another 6 weeks;

12 weeks

Clinical remission was obtained in 76.7% patients after 6 weeks and in 82.1% after 12 weeks of CDED. FCP improved vs baseline (P = .021).

Yanai 2022¹⁵

Adults (18-55 years) with mild—moderate CD (HBI 5-14) from Israel
(n = 44)

Open-label, pilot randomised trial

Group 1: CDED plus partial enteral nutrition Group 2: CDED alone for 24 weeks.

24 weeks

At week 6, CDED + PEN resulted in 68% remission rate and CDED alone resulted in 57% clinical remission. 80% of those in remission at week 6 sustained remission at week 24.

Fliss Isakov 2023³¹

Adults (>18 years) with active pouchitis: cPDAI > 2 and mPDAI ≥ 5 (n = 8) from Israel

Nonrandomized, noncontrolled, open-label, Interventional Pilot Study

CDED plus 50% PEN for 6 weeks followed by CDED with
25% PEN for another 6 weeks

12 weeks

Clinical remission (cPDAI subscore 2) was achieved by 66.7%, 60%, and 46.7% of patients at Weeks 6, 12, and 24, respectively.

Study	Study Population	Study Design	Intervention Group	Study Duration	Main Outcomes
Pediatric Studies
Sigall-Boneh 2014²²	Active CD patients from Israel, mostly mild to moderate disease. (n = 47; 13 were young adults)	Retrospective quasi-experiment	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks, or CDED alone	12 weeks	Clinical response and remission were achieved in 79% and 71%, respectively, at week 6. CRP was normalized in 70%
Sigall-Boneh 2017²³	CD patients with loss of response to biologics (n = 21; 11 were young adults)	Retrospective quasi-experiment	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks, or CDED alone. Severe patients started with EEN for 2 weeks and continued with CDED plus PEN	12 weeks	Clinical response and remission were achieved in 90% and 62%, respectively, and lead to improvement in inflammatory markers at week 6
Levine 2019¹⁴	Mild to moderate luminal CD patients from Israel and Canada (n = 78)	RCT	Group1: CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks; Group2: EEN for 6 weeks followed by a free diet with 25% PEN for another 6 weeks	12 weeks	CDED plus PEN was better tolerated than EEN and led to 75% clinical remission vs 59% in the EEN group at week 6; CDED + PEN was superior to EEN group at 12 weeks in all clinical parameters
Sigall-Boneh 2021²⁴	The same RCT¹⁴ cohort	Post hoc analysis	2 interventional groups as describe previously	12 weeks	Both groups (CDED and EEN) induced rapid responses (82% and 85% respectively) at week 3
Levine 2020²⁵	Active CD from Israel (n = 4)	Case Series	CDED plus PEN	Up to 3 years	Case 1 and 2: CDED plus PEN effective monotherapy in uncomplicated mild-moderate CD disease, with > 1 year sustained remission recorded. Case 3: In penetrating disease, CDED plus PEN effective as a combination maintenance therapy post induction of remission with 8/52 EEN, antibiotics and anti-TNF. Resolution of fistula and perianal disease at 4 months repeat MRE. Case 4: CDED and PEN effective as rescue therapy in refractory patient. Regained response to biologics and sustained remission at 5 months.
Scarallo 2021²⁶	Mild to moderate luminal-colonic CD patients from Italy	Cases series	CDED plus PEN or CDED alone	Up to 52 weeks	CDED with or withoutPEN presented a safe and effective therapeutic option asboth induction and maintenance monotherapy
Niseteo 2021¹⁷	Active CD patients from Croatia (n = 61)	Retrospective comparative study	2 interventional groups: EEN and CDED plus PEN. In the CDED plus PEN group, 80% of patients initially received EEN for 1-2 weeks.	6-8 weeks	CDED + PEN resulted in a 75% remission rate and was as effective as EEN in inducing remission and improved weight gain.
Matuszczyk 2022¹⁶	Mild-moderate CD patients with elevated FCP (n = 48) from Poland	Prospective quasi-experiment	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks	12 weeks	FCP levels were normalized in 35%; 50% decrease in FCP in 54%
Stein 2022²⁷	Remission CD (age 13-23 years) in Israel and USA (n = 18)	Prospective comparative study	Diets following withdrawal of immunomodulator or anti-TNF Group 1: CDED plus PEN Group 2: Free diet	52 weeks	No significant difference in 52-week remission rates (5/9; 55.6%) amongst CDED vs Free diet group (5/7; 71.4%), P = .63.
Martín-Masot 2023²⁸	Mild- moderate CD (age 8-18 years) from Spain (n = 24)	Prospective to assess changes in dietary habits on CDED and compliance after 1 year	24 hour recall at baseline and 52 weeks on CDED	52 weeks	CDED resulted in reduction in the intake of ultra-processed foods (UPFs); a higher adherence to the Mediterranean diet (KIDMED score: 5 ± 2.1 at baseline vs 7.5 ± 1.4 at 52 weeks. After 52 weeks of CDED treatment, no patient had a very poor-quality diet compared with 33.33% at baseline.
María Clara Jijón Andrade 2023²⁹	New onset mild to moderate and loss of response to biologics (age 10.7-15) from Spain (n = 15)	Retrospective quasi-experiment	CDED + PEN	24 Weeks	CDED + PEN among 15 patients with CD resulted in remission in all patients at week 6 and 12. Among them, 87% of treatment naïve patients-maintained remission at week 24 compared with 67% in patients who lost response to biologics. In treatment naïve patients the FCP and albumin improved at week 6, week 12, and week 24 (P < .05). Whereas in patients who loss response to biologics the reduction in FCP did not reach a level of significant.
Adult Studies
Szczubelek 2021³⁰	Adults with mild—severe CD CDAI > 150 (n = 32) from Poland	Real world evidence	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks;	12 weeks	Clinical remission was obtained in 76.7% patients after 6 weeks and in 82.1% after 12 weeks of CDED. FCP improved vs baseline (P = .021).
Yanai 2022¹⁵	Adults (18-55 years) with mild—moderate CD (HBI 5-14) from Israel (n = 44)	Open-label, pilot randomised trial	Group 1: CDED plus partial enteral nutrition Group 2: CDED alone for 24 weeks.	24 weeks	At week 6, CDED + PEN resulted in 68% remission rate and CDED alone resulted in 57% clinical remission. 80% of those in remission at week 6 sustained remission at week 24.
Fliss Isakov 2023³¹	Adults (>18 years) with active pouchitis: cPDAI > 2 and mPDAI ≥ 5 (n = 8) from Israel	Nonrandomized, noncontrolled, open-label, Interventional Pilot Study	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks	12 weeks	Clinical remission (cPDAI subscore 2) was achieved by 66.7%, 60%, and 46.7% of patients at Weeks 6, 12, and 24, respectively.

Study

Study Population

Study Design

Intervention Group

Study Duration

Main Outcomes

Pediatric Studies

Sigall-Boneh 2014²²

Active CD patients from Israel, mostly mild to moderate disease. (n = 47; 13 were young adults)

Retrospective quasi-experiment

CDED plus 50% PEN for 6 weeks followed by CDED with
25% PEN for another 6 weeks, or CDED alone

12 weeks

Clinical response and remission were achieved in 79% and 71%, respectively, at week 6. CRP was normalized in 70%

Sigall-Boneh 2017²³

CD patients with loss of response to biologics (n = 21; 11 were young adults)

Retrospective quasi-experiment

CDED plus 50% PEN for 6 weeks followed by CDED with
25% PEN for another 6 weeks, or CDED alone.
Severe patients started with EEN for 2 weeks and continued with CDED plus PEN

12 weeks

Clinical response and remission were achieved in 90% and 62%, respectively, and lead to improvement in inflammatory markers at week 6

Levine 2019¹⁴

Mild to moderate luminal CD patients from Israel and Canada (n = 78)

RCT

Group1: CDED plus 50% PEN for 6 weeks followed by CDED with
25% PEN for another 6 weeks; Group2: EEN for 6 weeks followed by a free diet with 25% PEN for another 6 weeks

12 weeks

CDED plus PEN was better tolerated than EEN and led to 75% clinical remission vs 59% in the EEN group at week 6; CDED + PEN was superior to EEN group at 12 weeks in all clinical parameters

Sigall-Boneh 2021²⁴

The same RCT¹⁴ cohort

Post hoc analysis

2 interventional groups as describe previously

12 weeks

Both groups (CDED and EEN) induced rapid responses (82% and 85% respectively) at week 3

Levine 2020²⁵

Active CD from Israel
(n = 4)

Case Series

CDED plus PEN

Up to 3 years

Scarallo 2021²⁶

Mild to moderate luminal-colonic CD patients from Italy

Cases series

CDED plus PEN or CDED alone

Up to 52 weeks

CDED with or withoutPEN presented a safe and effective therapeutic option asboth induction and maintenance monotherapy

Niseteo 2021¹⁷

Active CD patients from Croatia (n = 61)

Retrospective comparative study

2 interventional groups: EEN and CDED plus PEN. In the CDED plus PEN group, 80% of patients initially received EEN for 1-2 weeks.

6-8 weeks

CDED + PEN resulted in a 75% remission rate and was as effective as EEN in inducing remission and improved weight gain.

Matuszczyk 2022¹⁶

Mild-moderate CD patients with elevated FCP (n = 48) from Poland

Prospective quasi-experiment

CDED plus 50% PEN for 6 weeks followed by CDED with
25% PEN for another 6 weeks

12 weeks

FCP levels were normalized in 35%; 50% decrease in FCP in 54%

Stein 2022²⁷

Remission CD (age 13-23 years) in Israel and USA
(n = 18)

Prospective comparative study

Diets following withdrawal of immunomodulator or anti-TNF
Group 1: CDED plus PEN
Group 2: Free diet

52 weeks

No significant difference in 52-week remission rates (5/9; 55.6%) amongst CDED vs Free diet group (5/7; 71.4%), P = .63.

Martín-Masot 2023²⁸

Mild- moderate CD
(age 8-18 years) from Spain (n = 24)

Prospective to assess changes in dietary habits on CDED and compliance after 1 year

24 hour recall at baseline and 52 weeks on CDED

52 weeks

María Clara Jijón Andrade 2023²⁹

New onset mild to moderate and loss of response to biologics (age 10.7-15) from Spain (n = 15)

Retrospective quasi-experiment

CDED + PEN

24 Weeks

Adult Studies

Szczubelek 2021³⁰

Adults with mild—severe CD CDAI > 150 (n = 32) from Poland

Real world evidence

CDED plus 50% PEN for 6 weeks followed by CDED with
25% PEN for another 6 weeks;

12 weeks

Clinical remission was obtained in 76.7% patients after 6 weeks and in 82.1% after 12 weeks of CDED. FCP improved vs baseline (P = .021).

Yanai 2022¹⁵

Adults (18-55 years) with mild—moderate CD (HBI 5-14) from Israel
(n = 44)

Open-label, pilot randomised trial

Group 1: CDED plus partial enteral nutrition Group 2: CDED alone for 24 weeks.

24 weeks

At week 6, CDED + PEN resulted in 68% remission rate and CDED alone resulted in 57% clinical remission. 80% of those in remission at week 6 sustained remission at week 24.

Fliss Isakov 2023³¹

Adults (>18 years) with active pouchitis: cPDAI > 2 and mPDAI ≥ 5 (n = 8) from Israel

Nonrandomized, noncontrolled, open-label, Interventional Pilot Study

CDED plus 50% PEN for 6 weeks followed by CDED with
25% PEN for another 6 weeks

12 weeks

Clinical remission (cPDAI subscore 2) was achieved by 66.7%, 60%, and 46.7% of patients at Weeks 6, 12, and 24, respectively.

Table 1.

Open in new tab

Summary of CDED clinical studies and evidence.

Study	Study Population	Study Design	Intervention Group	Study Duration	Main Outcomes
Pediatric Studies
Sigall-Boneh 2014²²	Active CD patients from Israel, mostly mild to moderate disease. (n = 47; 13 were young adults)	Retrospective quasi-experiment	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks, or CDED alone	12 weeks	Clinical response and remission were achieved in 79% and 71%, respectively, at week 6. CRP was normalized in 70%
Sigall-Boneh 2017²³	CD patients with loss of response to biologics (n = 21; 11 were young adults)	Retrospective quasi-experiment	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks, or CDED alone. Severe patients started with EEN for 2 weeks and continued with CDED plus PEN	12 weeks	Clinical response and remission were achieved in 90% and 62%, respectively, and lead to improvement in inflammatory markers at week 6
Levine 2019¹⁴	Mild to moderate luminal CD patients from Israel and Canada (n = 78)	RCT	Group1: CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks; Group2: EEN for 6 weeks followed by a free diet with 25% PEN for another 6 weeks	12 weeks	CDED plus PEN was better tolerated than EEN and led to 75% clinical remission vs 59% in the EEN group at week 6; CDED + PEN was superior to EEN group at 12 weeks in all clinical parameters
Sigall-Boneh 2021²⁴	The same RCT¹⁴ cohort	Post hoc analysis	2 interventional groups as describe previously	12 weeks	Both groups (CDED and EEN) induced rapid responses (82% and 85% respectively) at week 3
Levine 2020²⁵	Active CD from Israel (n = 4)	Case Series	CDED plus PEN	Up to 3 years	Case 1 and 2: CDED plus PEN effective monotherapy in uncomplicated mild-moderate CD disease, with > 1 year sustained remission recorded. Case 3: In penetrating disease, CDED plus PEN effective as a combination maintenance therapy post induction of remission with 8/52 EEN, antibiotics and anti-TNF. Resolution of fistula and perianal disease at 4 months repeat MRE. Case 4: CDED and PEN effective as rescue therapy in refractory patient. Regained response to biologics and sustained remission at 5 months.
Scarallo 2021²⁶	Mild to moderate luminal-colonic CD patients from Italy	Cases series	CDED plus PEN or CDED alone	Up to 52 weeks	CDED with or withoutPEN presented a safe and effective therapeutic option asboth induction and maintenance monotherapy
Niseteo 2021¹⁷	Active CD patients from Croatia (n = 61)	Retrospective comparative study	2 interventional groups: EEN and CDED plus PEN. In the CDED plus PEN group, 80% of patients initially received EEN for 1-2 weeks.	6-8 weeks	CDED + PEN resulted in a 75% remission rate and was as effective as EEN in inducing remission and improved weight gain.
Matuszczyk 2022¹⁶	Mild-moderate CD patients with elevated FCP (n = 48) from Poland	Prospective quasi-experiment	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks	12 weeks	FCP levels were normalized in 35%; 50% decrease in FCP in 54%
Stein 2022²⁷	Remission CD (age 13-23 years) in Israel and USA (n = 18)	Prospective comparative study	Diets following withdrawal of immunomodulator or anti-TNF Group 1: CDED plus PEN Group 2: Free diet	52 weeks	No significant difference in 52-week remission rates (5/9; 55.6%) amongst CDED vs Free diet group (5/7; 71.4%), P = .63.
Martín-Masot 2023²⁸	Mild- moderate CD (age 8-18 years) from Spain (n = 24)	Prospective to assess changes in dietary habits on CDED and compliance after 1 year	24 hour recall at baseline and 52 weeks on CDED	52 weeks	CDED resulted in reduction in the intake of ultra-processed foods (UPFs); a higher adherence to the Mediterranean diet (KIDMED score: 5 ± 2.1 at baseline vs 7.5 ± 1.4 at 52 weeks. After 52 weeks of CDED treatment, no patient had a very poor-quality diet compared with 33.33% at baseline.
María Clara Jijón Andrade 2023²⁹	New onset mild to moderate and loss of response to biologics (age 10.7-15) from Spain (n = 15)	Retrospective quasi-experiment	CDED + PEN	24 Weeks	CDED + PEN among 15 patients with CD resulted in remission in all patients at week 6 and 12. Among them, 87% of treatment naïve patients-maintained remission at week 24 compared with 67% in patients who lost response to biologics. In treatment naïve patients the FCP and albumin improved at week 6, week 12, and week 24 (P < .05). Whereas in patients who loss response to biologics the reduction in FCP did not reach a level of significant.
Adult Studies
Szczubelek 2021³⁰	Adults with mild—severe CD CDAI > 150 (n = 32) from Poland	Real world evidence	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks;	12 weeks	Clinical remission was obtained in 76.7% patients after 6 weeks and in 82.1% after 12 weeks of CDED. FCP improved vs baseline (P = .021).
Yanai 2022¹⁵	Adults (18-55 years) with mild—moderate CD (HBI 5-14) from Israel (n = 44)	Open-label, pilot randomised trial	Group 1: CDED plus partial enteral nutrition Group 2: CDED alone for 24 weeks.	24 weeks	At week 6, CDED + PEN resulted in 68% remission rate and CDED alone resulted in 57% clinical remission. 80% of those in remission at week 6 sustained remission at week 24.
Fliss Isakov 2023³¹	Adults (>18 years) with active pouchitis: cPDAI > 2 and mPDAI ≥ 5 (n = 8) from Israel	Nonrandomized, noncontrolled, open-label, Interventional Pilot Study	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks	12 weeks	Clinical remission (cPDAI subscore 2) was achieved by 66.7%, 60%, and 46.7% of patients at Weeks 6, 12, and 24, respectively.

Study	Study Population	Study Design	Intervention Group	Study Duration	Main Outcomes
Pediatric Studies
Sigall-Boneh 2014²²	Active CD patients from Israel, mostly mild to moderate disease. (n = 47; 13 were young adults)	Retrospective quasi-experiment	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks, or CDED alone	12 weeks	Clinical response and remission were achieved in 79% and 71%, respectively, at week 6. CRP was normalized in 70%
Sigall-Boneh 2017²³	CD patients with loss of response to biologics (n = 21; 11 were young adults)	Retrospective quasi-experiment	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks, or CDED alone. Severe patients started with EEN for 2 weeks and continued with CDED plus PEN	12 weeks	Clinical response and remission were achieved in 90% and 62%, respectively, and lead to improvement in inflammatory markers at week 6
Levine 2019¹⁴	Mild to moderate luminal CD patients from Israel and Canada (n = 78)	RCT	Group1: CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks; Group2: EEN for 6 weeks followed by a free diet with 25% PEN for another 6 weeks	12 weeks	CDED plus PEN was better tolerated than EEN and led to 75% clinical remission vs 59% in the EEN group at week 6; CDED + PEN was superior to EEN group at 12 weeks in all clinical parameters
Sigall-Boneh 2021²⁴	The same RCT¹⁴ cohort	Post hoc analysis	2 interventional groups as describe previously	12 weeks	Both groups (CDED and EEN) induced rapid responses (82% and 85% respectively) at week 3
Levine 2020²⁵	Active CD from Israel (n = 4)	Case Series	CDED plus PEN	Up to 3 years	Case 1 and 2: CDED plus PEN effective monotherapy in uncomplicated mild-moderate CD disease, with > 1 year sustained remission recorded. Case 3: In penetrating disease, CDED plus PEN effective as a combination maintenance therapy post induction of remission with 8/52 EEN, antibiotics and anti-TNF. Resolution of fistula and perianal disease at 4 months repeat MRE. Case 4: CDED and PEN effective as rescue therapy in refractory patient. Regained response to biologics and sustained remission at 5 months.
Scarallo 2021²⁶	Mild to moderate luminal-colonic CD patients from Italy	Cases series	CDED plus PEN or CDED alone	Up to 52 weeks	CDED with or withoutPEN presented a safe and effective therapeutic option asboth induction and maintenance monotherapy
Niseteo 2021¹⁷	Active CD patients from Croatia (n = 61)	Retrospective comparative study	2 interventional groups: EEN and CDED plus PEN. In the CDED plus PEN group, 80% of patients initially received EEN for 1-2 weeks.	6-8 weeks	CDED + PEN resulted in a 75% remission rate and was as effective as EEN in inducing remission and improved weight gain.
Matuszczyk 2022¹⁶	Mild-moderate CD patients with elevated FCP (n = 48) from Poland	Prospective quasi-experiment	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks	12 weeks	FCP levels were normalized in 35%; 50% decrease in FCP in 54%
Stein 2022²⁷	Remission CD (age 13-23 years) in Israel and USA (n = 18)	Prospective comparative study	Diets following withdrawal of immunomodulator or anti-TNF Group 1: CDED plus PEN Group 2: Free diet	52 weeks	No significant difference in 52-week remission rates (5/9; 55.6%) amongst CDED vs Free diet group (5/7; 71.4%), P = .63.
Martín-Masot 2023²⁸	Mild- moderate CD (age 8-18 years) from Spain (n = 24)	Prospective to assess changes in dietary habits on CDED and compliance after 1 year	24 hour recall at baseline and 52 weeks on CDED	52 weeks	CDED resulted in reduction in the intake of ultra-processed foods (UPFs); a higher adherence to the Mediterranean diet (KIDMED score: 5 ± 2.1 at baseline vs 7.5 ± 1.4 at 52 weeks. After 52 weeks of CDED treatment, no patient had a very poor-quality diet compared with 33.33% at baseline.
María Clara Jijón Andrade 2023²⁹	New onset mild to moderate and loss of response to biologics (age 10.7-15) from Spain (n = 15)	Retrospective quasi-experiment	CDED + PEN	24 Weeks	CDED + PEN among 15 patients with CD resulted in remission in all patients at week 6 and 12. Among them, 87% of treatment naïve patients-maintained remission at week 24 compared with 67% in patients who lost response to biologics. In treatment naïve patients the FCP and albumin improved at week 6, week 12, and week 24 (P < .05). Whereas in patients who loss response to biologics the reduction in FCP did not reach a level of significant.
Adult Studies
Szczubelek 2021³⁰	Adults with mild—severe CD CDAI > 150 (n = 32) from Poland	Real world evidence	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks;	12 weeks	Clinical remission was obtained in 76.7% patients after 6 weeks and in 82.1% after 12 weeks of CDED. FCP improved vs baseline (P = .021).
Yanai 2022¹⁵	Adults (18-55 years) with mild—moderate CD (HBI 5-14) from Israel (n = 44)	Open-label, pilot randomised trial	Group 1: CDED plus partial enteral nutrition Group 2: CDED alone for 24 weeks.	24 weeks	At week 6, CDED + PEN resulted in 68% remission rate and CDED alone resulted in 57% clinical remission. 80% of those in remission at week 6 sustained remission at week 24.
Fliss Isakov 2023³¹	Adults (>18 years) with active pouchitis: cPDAI > 2 and mPDAI ≥ 5 (n = 8) from Israel	Nonrandomized, noncontrolled, open-label, Interventional Pilot Study	CDED plus 50% PEN for 6 weeks followed by CDED with 25% PEN for another 6 weeks	12 weeks	Clinical remission (cPDAI subscore 2) was achieved by 66.7%, 60%, and 46.7% of patients at Weeks 6, 12, and 24, respectively.

Abbreviations: RCT, randomized controlled trial; CDED, Crohn’s disease exclusion diet; PEN, partial enteral nutrition; EEN, exclusive enteral nutrition, CDAI: Crohn’s disease activity index, cPDAI: clinical Pouchitis Disease Activity Index IBDQ: IBD quality of life, mPDAI modified Pouchitis Disease Activity Index: HBI: Harvey Bradshaw Index; FCP-Fecal calprotectin.

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