The Efficacy of Cobitolimod in Patients With Moderate to Severe Active Ulcerative Colitis

This was a Phase IIb study in patients with moderate to severe left-sided ulcerative colitis. Patients either received cobitolimod 31 mg, 125 mg or 250 mg at two occasions or 125 mg or placebo at four occasions during a 3-weeks period. To ensure blindness, patients received active treatment at two occasions and placebo at the other two occasions. Blood, stool, and tissue samples was collected at various time points throughout the study to evaluate safety and efficacy. Primary endpoint was evaluated at week 6.

Duration of participation for patients was approximately 12 weeks (from screening to final follow-up visit).

• cobitolimod (Drug), also known as Kappaproct: Rectal administration
• Placebo (Drug), also known as Placebo (for cobitolimod): Solution manufactured to mimic cobitolimod

Primary outcomes

• Clinical Remission [6 weeks after first treatment]: Patients with clinical remission at Week 6 (yes=1, no=0), defined by Modified Mayo sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0), and iii) endoscopy score of 0 or 1 (excluding friability).

Secondary outcomes

• Modified Clinical Remission [Week 6]: Patients with modified clinical remission at Week 6 (yes=1, no=0), defined by the Modified Mayo score ≤ 2 and sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0), iii) endoscopy score of 0 or 1 (excluding friability ) and iiii) physician´s global assessment (PGA) of 0 or 1
• Symptomatic Remission [Week 6]: Patients with symptomatic remission at Week 6 (yes=1, no=0), defined by the Mayo sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0), (patient reported outcome)
• Clinical Response [Week 6]: Patients with clinical response at Week 6 (yes=1, no=0), defined as clinical remission or a three point and ≥30 % decrease from Baseline, Week 0 in the sum of the Modified Mayo score, i) rectal bleeding, ii) stool frequency and iii) endoscopy score (excluding friability), iiii) physicians global assessment (PGA)
• Endoscopic Remission [Week 6]: Patients with endoscopic remission at Week 6 (yes=1, no=0), defined by the Modified Mayo endoscopic sub score of 0 or 1 (excluding friability)
• Histological Remission [Week 6]: Patients with histological remission at Week 6 (yes=1, no=0), defined by the Nancy histological index of grade 0 or 1

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age ≥ 18 years old
* Established diagnosis of Ulcerative Colitis (UC)
* Moderately to severely active left sided UC assessed by central reading
* Current oral 5-Aminosalicylic Acid (5-ASA)/ Sulphasalazine (SP) use or a history of oral 5-ASA/SP use
* Current Glucocorticosteroids (GCS) use or history of GCS dependency, refractory, or intolerance
* Demonstrated an inadequate response, loss of response, or intolerance to at least one of the following agents:

  * Immunomodulators
  * Tumor Necrosis Factor alpha (TNF-α) inhibitors and/or anti-integrins

Exclusion Criteria:

* Suspicion of differential diagnosis
* Acute fulminant UC and/or signs of systemic toxicity
* UC limited to the rectum (disease which extend <15 cm above the anal verge)
* History of malignancy
* History or presence of any clinically significant disorder
* Concomitant treatment with cyclosporine, methotrexate, tacrolimus, TNF-α inhibitors, anti-integrins or similar immunosuppressants and immunomodulators
* Treatment with rectal GCS, 5-ASA/SP or tacrolimus
* Long term treatment with antibiotics or non-steroidal anti-inflammatory drugs (NSAIDs)
* Serious active infection
* Gastrointestinal infections
* Currently receiving parenteral nutrition or blood transfusions
* Females who are lactating or have a positive serum pregnancy test
* Women of childbearing potential not using reliable contraceptive methods
* Concurrent participation in another clinical study
* Previous exposure to cobitolimod

Participant flow

Outcome results

• Clinical Remission (Primary), Count of participants, Participants: Cobitolimod Dose 2x31 mg 5; Cobitolimod Dose 2x125 mg 2; Cobitolimod Dose 2x250 mg 9; Cobitolimod Dose 4x125 mg 4; Placebo 3 (p 0.1806)
• Modified Clinical Remission (Secondary), Count of participants, Participants: Cobitolimod Dose 2x31 mg 5; Cobitolimod Dose 2x125 mg 1; Cobitolimod Dose 2x250 mg 7; Cobitolimod Dose 4x125 mg 3; Placebo 3 (p 0.2115)
• Symptomatic Remission (Secondary), Count of participants, Participants: Cobitolimod Dose 2x31 mg 10; Cobitolimod Dose 2x125 mg 11; Cobitolimod Dose 2x250 mg 13; Cobitolimod Dose 4x125 mg 10; Placebo 9 (p 0.2335)
• Clinical Response (Secondary), Count of participants, Participants: Cobitolimod Dose 2x31 mg 17; Cobitolimod Dose 2x125 mg 18; Cobitolimod Dose 2x250 mg 20; Cobitolimod Dose 4x125 mg 15; Placebo 20 (p 0.6326)
• Endoscopic Remission (Secondary), Count of participants, Participants: Cobitolimod Dose 2x31 mg 7; Cobitolimod Dose 2x125 mg 5; Cobitolimod Dose 2x250 mg 15; Cobitolimod Dose 4x125 mg 10; Placebo 12 (p 0.7994)
• Histological Remission (Secondary), Count of participants, Participants: Cobitolimod Dose 2x31 mg 4; Cobitolimod Dose 2x125 mg 5; Cobitolimod Dose 2x250 mg 8; Cobitolimod Dose 4x125 mg 7; Placebo 10 (p 0.9207)

Adverse events

Time frame: Adverse Event (AE) was collected from the date of signed informed consent. During the screening period up to first treatment only AEs related to a study specific procedures should be reported. AEs were reported up to follow up visit at Week 10 (from first treatment)

Serious adverse events by term

Other adverse events by term

• Results publication: Atreya R, Peyrin-Biroulet L, Klymenko A, Augustyn M, Bakulin I, Slankamenac D, Miheller P, Gasbarrini A, Hebuterne X, Arnesson K, Knittel T, Kowalski J, Neurath MF, Sandborn WJ, Reinisch W; CONDUCT study group. Cobitolimod for moderate-to-severe, left-sided ulcerative colitis (CONDUCT): a phase 2b randomised, double-blind, placebo-controlled, dose-ranging induction trial. Lancet Gastroenterol Hepatol. 2020 Dec;5(12):1063-1075. doi: 10.1016/S2468-1253(20)30301-0. Epub 2020 Oct 5. PMID 33031757

• Study Protocol and Statistical Analysis Plan (PDF, 2017-01-19)

• Raja Atreya, Principal investigator, Friedrich-Alexander University Erlangen-Nuremberg

NIH grants: 2016