E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic sclerosis (SSc) is a rare, complex, multi-organ disorder characterized by immune-mediated inflammation, progressive organ fibrosis and vascular pathology leading to small vessel obliteration. Gastrointestinal tract (GIT) affliction occurs in 9/10 SSc patients, involves all parts of the GIT and impairs key GIT functions such as motility, absorption and sphincter control. GIT symptoms impact quality of life in SSc, and severe GIT afflictions are among the leading causes of death in SSc. |
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E.1.1.1 | Medical condition in easily understood language |
Systemic sclerosis (SSc) is a rare, complex, multi-organ disorder characterized by immune-mediated inflammation, progressive organ fibrosis and vascular pathology leading to small vessel obliteration. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042953 |
E.1.2 | Term | Systemic sclerosis |
E.1.2 | System Organ Class | 100000004859 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary and secondary endpoints of the ReSScue trial will be estimated at week 12, which represents the end of study period 1, while safety and tolerability will be assessed throughout the 26 week study period. In addition, a number of explorative clinical endpoints will be assessed at weeks 12 and 26. The study is designed with repeat scheduled samplings of biological materials, allowing for explorative endpoints on biomarkers during study periods 1 and 2, and later development of research studies at molecular level (see Section 8).
• Estimate efficacy of ACHIM compared to placebo on lower GIT symptoms |
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E.2.2 | Secondary objectives of the trial |
• Assess safety and tolerability of intestinal ACHIM infusions in participants with SSc
• Estimate efficacy of ACHIM compared to placebo on overall GIT symptoms
• Estimate effects of ACHIM compared to placebo on fecal soilage episodes from baseline through week 12
• Estimate efficacy of ACHIM compared to placebo on SSc disease activity.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Age
1. Participant must be 18 to 85 years of age inclusive, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Participants must have been clinically diagnosed with SSc by a rheumatologist having experience with the disease.
3. Participants must have disease characteristics that fulfill the 2013 ACR/EULAR classification criteria for SSc.
4. Participants must be able to understand and follow trial procedures including completion of questionnaires regarding Patient Reported Outcome measures, such as the Norwegian version of the UCLA GIT V2.0 score.
5. Participants must have moderate to severe SSc-related lower GI symptoms at time of inclusion, as defined by UCLA GIT score values of ≥1.01 for bloating and/or ≥0.50 for diarrhea at the screening visit.
Sex
6. Male and female
Informed Consent
7. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
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E.4 | Principal exclusion criteria |
Medical Conditions
1. Cardiovascular diseases, any of the following
a. Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 6 month of Visit 1
b. Myocardial infarction within 6 months of Visit 1
c. Unstable cardiac angina within 6 months of Visit 1
2. Lung disease with impaired respiratory function, any of the following
a. Forced Vital Capacity (FVC) < 50% of expected reference value within 12 month of Visit 1
b. Diffusing lung capacity for carbon monoxide (DLCO) < 40% of expected reference value within 12 month of Visit 1
c. LTOT or lung-tx
3. Significant pulmonary hypertension, any of the following
a. Previous clinical or echocardiographic evidence of significant right heart failure
b. History of right heart catheterisation showing a cardiac index ≤ 2 l/min/m²
4. History of thrombotic event (including stroke and transient ischemic attack) within 12 months of Visit 1
5. Severe anemia with Hb < 8.0 g/l within 4 weeks prior to Visit 1. Repeat testing of Hb is allowed.
6. Bleeding risk, any of the following
a. History of hemorrhagic central nervous system (CNS) event within 1 month of Visit 1.
b. Known genetic predisposition to bleeding
c. Platelet counts < 50 x 109/l
7. Chronic liver disease or gastro-intestinal condition, any of the following
a. Primary biliary cholangitis
b. Primary sclerosing cholangitis
c. Decompensated chronic liver disease
d. Inflammatory bowel disease
e. Celiac disease treated for less than 12 months.
8. Gastro-intestinal surgery performed within the within 12 months of Visit 1
9. Hepatic dysfunction, as defined as AST, ALT or bilirubin levels >3 times the Upper limit of normal range (x ULN) within 4 weeks prior to Visit 1. Repeat testing of AST, ALT and bilirubin are allowed in participants with no prior history of hepatic dysfunction.
10. Chronic renal insufficiency, with estimated Glomerular Filtration Rate (eGFR) < 30.
11. Active digital ulcers within 4 weeks of Visit 1.
12. Eating disorder diagnosed by a physician
13. Other diseases or conditions that may interfere with testing procedures (for example inability to conduct gastroduodenoscopy) or in the judgment of the Investigator may interfere with trial participation or may put the patient at risk when participating in this trial (for example severe GI symptoms due to other diseases than SSc).
Prior/Concomitant Therapy
14. Any antibiotic therapy within 3 months of Visit 1
15. Prednisone >10 mg/day or equivalent within 4 weeks prior to Visit 1
16. Cyclophosphamide or rituximab treatment within 6 months prior to Visit 1
17. Unstable background monotherapy with any of the following therapeutics; mycophenolate mofetil/sodium, methotrexate, azathioprine, tocilizumab, abatacept, leflunomide, tacrolimus, tofacitinib and cyclosporine A. Participants have to be on stable monotherapy with any of these medications for at least 6 months prior to visit 1
18. Combined therapy of two or more of the following therapeutics: mycophenolate mofetil/sodium, methotrexate, azathioprine, tocilizumab, abatacept, leflunomide, tacrolimus, tofacitinib and ciclosporine A within at least 8 weeks prior to visit 1.
19. Need for full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors or heparin)
20. Previous hematopoietic stem cell transplantation (HSCT) within 12 months of Visit 1, or HSCT planned within 12 months after Visit 1.
21. Other investigational therapy received within 1 month or 6 half-lives (whichever was greater) prior to screening visit.
Prior/Concurrent Clinical Study Experience
22. Prior participation in FMT study in the last 12 months.
Diagnostic assessments
23. Abnormal coagulation parameters as defined as International normalised ratio (INR) >2, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT) by >1.5 x ULN at Visit 1
Other Exclusions
24. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
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E.5 End points |
E.5.1 | Primary end point(s) |
• Change from baseline to week 12 in mean of UCLA GIT score items diarrhea and bloating |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary and secondary endpoints of the ReSScue trial will be estimated at week 12, which represents the end of study period 1 |
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E.5.2 | Secondary end point(s) |
• Safety and tolerability assessed by adverse event (AE) monitoring, physical examination, vital signs, clinical laboratory testing and electrocardiogram during the entire 26 week study period.
• Change from baseline to week 12 in total UCLA GIT score
• Fecal incontinence quality of life scale Norwegian version at screening, week 6 and week 12.
• Change from baseline to week 12 in the validated SSc disease activity index (SSc-DAI)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary and secondary endpoints of the ReSScue trial will be estimated at week 12, which represents the end of study period 1 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the date of the last follow-up visit of the last participant in the study (LVLS). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |