E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010759 |
E.1.2 | Term | Connective tissue disorder NOS |
E.1.2 | System Organ Class | 100000004859 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018124 |
E.1.2 | Term | Generalized scleroderma |
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 |
1.To identify any effects of factor XIII treatment on clinical manifestations of Sleroderma (SSc) 2.To investigate factor XIII safety 3.To measure individual factor XIII levels in patients with SSc 4.To measure the effects of factor XIII treatment on factor XIII PK parameters.
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E.2.2 | Secondary objectives of the trial |
1.To explore effects of factor XIII on thrombospondin expression |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.≥ 18 years 2.Male and female adults 3.Subjects with a diagnosis of SSc according to the 2013 ACR EULAR classification criteria.They will be classified according to LeRoy criteria as limited or diffuse subset. 4.Females of childbearing potential must be willing to use a reliable form of medically acceptable contraception and have a negative pregnancy test 5.Subjects will have serological status for hepatitis A and B assessed at screening. 6.Patients who have given their free and informed consent
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E.4 | Principal exclusion criteria |
1.Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time consent is signed until 6 weeks after treatment discontinuation. 2.Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for trial treatment. NOTE: Subjects are considered not of child bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal. 3.Females must not be breastfeeding. 4.Allergies to excipients of IMP and placebo 5.Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure > 160 mmHg or sitting diastolic blood pressure > 100 mmHg. 6.Portal hypertension or chronic liver disease defined as mild to severe hepatic impairment (Child-Pugh Class A-C). Subjects positive for Hepatitis C with evidence of active viral replication on sensitive PCR testing are also excluded. 7.Hepatic dysfunction, defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 3 times the upper limit of the normal range (× ULN) at the Screening Visit. 8.Chronic renal insufficiency as defined by a serum creatinine > 2.5 mg/dL or requires dialysis. 9.Hemoglobin concentration < 10 g/dL at the Screening Visit. 10.History of left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following: 11.Aortic or mitral valve disease (stenosis or regurgitation) defined as more than minimum aortic insufficiency and more than moderate mitral regurgitation; (stenosis or regurgitation>grade 1)Pericardial constriction; Restrictive or congestive cardiomyopathy; Left ventricular ejection fraction 40 % by multiple gated acquisition scan 12.(MUGA), angiography, or echocardiography; Left ventricular shortening fraction < 22 % by echocardiography; or Symptomatic coronary disease with demonstrable ischemia. 13.History of malignancies within 5 years of Screening Visit with the exception of localized skin or cervical carcinomas. 14.Psychiatric, addictive, or other disorder that compromises the ability to give informed consent for participating in this study. This includes subjects with a recent history of abusing alcohol or illicit drugs 15. Ongoing treatment with hyperbaric oxygen 16.Exclude PAH patients 17.Patients who have received IV Iloprost within the last 2 months (1 to 3 months, to discuss) 18.Patients who have been treated with sypathectomy or toxin botulinum A within the last 3 months 19.Patients with a recent thrombosis, stroke, pulmonary embolism or myocardial infarction in the last 6 months 20.Patients with a diagnosis of diabetes mellitus requiring dietary restriction of cardbohydrate. 21.Patients having low sodium diet on medical advice. 22.Patients participating in another clinical trial involving an investigational medicinal product. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoints: •Skin involvement measured with modified Rodnan skin score •Raynaud condition score
Treatment Failure: •Rapid progression of skin involvement defined as more than 8 skin score units and 40% increase. •Rapid progression of lung involvement defined as 15% fall in FVC or 20% call in DLco •DU evolution to gangrene •Autoamputation or surgery for digital ulcer management (amputation) •hospitalization
Safety endpoints
•Physical examination (including height, weight, BMI, digital ulcer characterization) •Adverse events •Serious adverse events •ECG •Vital signs •Clinical laboratory parameters •Pregnancy •Adverse events of special interest: thromboembolic events
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
This is an early phase exploratory study and so all analysis will be descriptive and examine summary statistics and confidence intervals. Formal significance testing will not be undertaken and this will not be hypothesis testing. |
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E.5.2 | Secondary end point(s) |
Secondary Exploratory Analyses: •Pulmonary function •Hand function measured with Cochin hand function •Quality of life measured with SF36 quality of life questionnaire •Prevention of new DU: Number of new DU developed during a 24-week period of treatment •Healing of DU: Complete healing of DUs present at baseline; each DU is considered as an entity DU Pain assessment at 4, 8, 12, 16, 24 weeks of treatment: Pain will be assessed by analogue scale for pain (VAS) and Raynaud’s severity (Raynaud’s condition score) DU worsening, defined as: oOvernight Hospitalization for digital ulcers oAddition surgical treatment for digital ulcer in outpatient clinic oDigital ulcer infection oGangrene and/or amputation oNeed of local sympathectomy oNeed of toxin botulinum A) oNeed of oral or parenteral antibiotic oNeed of IV Iloprost : this is considered treatment failure
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
This is an early phase exploratory study and so all analysis will be descriptive and examine summary statistics and confidence intervals. Formal significance testing will not be undertaken and this will not be hypothesis testing. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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 | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |