A SAD/MAD Study of Safety, Tolerability and Pharmacologic Activity of BT200 in Normal Volunteers

Study Overview
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Brief Summary
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Study BT200-01 is a first in human (FIH) study in male and female normal human volunteers (NHVs) that uses an Integrated Protocol Design. This Phase 1 study will comprise 4 sub-parts: Part A, a single ascending dose (SAD) study; Part B, a multiple ascending dose (MAD) study; Part C, a desmopressin challenge study to explore (i) whether desmopressin could be used as an antidote, and/or (ii) whether desmopressin stimulated vonWillebrand Factor (VWF) release is overcome with increasing BT200 doses; and Part D, a relative bioavailability (BA) study. The primary objective of this study is to assess the safety and tolerability profile of BT200 in NHVs.

Official Title
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A Single/Multiple Ascending Dose Phase 1 Study of the Safety, Tolerability and Pharmacologic Activity of BT200 in Normal Human Volunteers

Conditions
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Cerebrovascular Stroke, Large-Artery Atherosclerosis (Embolus/Thrombosis), Intracranial Arteriosclerosis

Intervention / Treatment
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* Drug: BT200
* Drug: Desmopressin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or female volunteers, age ≥ 18 years old at screening If female, must be post-menopausal or status post hysterectomy Able to comprehend and to give informed consent Able to cooperate with the Investigator, to comply with the requirements of the study, and to complete the full sequence of protocol-related procedures Exclusion Criteria: Clinically significant medical history (including von Willebrand Disease, thrombocytopathy, or any type of bleeding diathesis) or ongoing chronic illness that would jeopardize the safety of the subject or compromise the quality of the data derived from his/her participation in this study Clinically relevant abnormal findings on physical examination or clinically relevant laboratory abnormalities History of infusion hypersensitivity reactions, significant drug allergy, or anaphylactic reactions Substance abuse, mental illness, or any reason that makes it unlikely in the judgment of the Investigator for the subject to be able to comply fully with study procedures Use of medication during 2 weeks before the start of the study, which in the judgment of the Investigator may adversely affect the subject's welfare or the integrity of the study's results Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days or 5 elimination half-lives (whichever is longer) prior to treatment start

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BT200 0.18mg<br>Subjects will receive a single subcutaneous dose of BT200 0.18mg | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>|
| Experimental: BT200 0.6mg<br>Subjects will receive a single subcutaneous dose of BT200 0.6mg | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>|
| Experimental: BT200 1.8mg<br>Subjects will receive a single subcutaneous dose of BT200 1.8mg | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>|
| Experimental: BT200 6.0mg<br>Subjects will receive a single subcutaneous dose of BT200 6.0mg | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>|
| Experimental: BT200 12.0mg<br>Subjects will receive a single subcutaneous dose of BT200 12.0mg | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>|
| Experimental: BT200 24.0mg<br>Subjects will receive a single subcutaneous dose of BT200 24.0mg | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>|
| Experimental: BT200 24.0mg rep<br>Subjects will receive a single subcutaneous (SC) dose of BT200 24.0mg by gradual SC infusion | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>|
| Placebo Comparator: Placebo SAD<br>Subjects will receive a single subcutaneous dose of placebo | Drug: Placebo<br>* Sterile saline for injection<br>|
| Experimental: BT200 loading dose 24.0mg, maintenance doses of 12.0 mg<br>Subjects will receive an initial subcutaneous loading doses of BT200 24.0mg followed by 4 weekly (every 7 days) maintenance doses of BT200 12.0mg | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>|
| Experimental: BT200 loading doses 48.0mg, maintenance doses of 24.0 mg<br>Subjects will receive an initial subcutaneous loading dose of BT200 48mg followed by 4 weekly (every 7 days) maintenance doses of BT200 24mg | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>|
| Placebo Comparator: Placebo MAD<br>Subjects will receive an initial subcutaneous loading dose of Placebo followed by 4 weekly (every 7 days) maintenance doses of placebo | Drug: Placebo<br>* Sterile saline for injection<br>|
| Experimental: BT200 48.0mg + desmopressin challenge<br>Subjects will receive a single subcutaneous dose of BT200 48.0mg followed by IV infusion (over 30 min) of 0.3µg/kg desmopressin administered 24 hours after single dose of BT200 | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>Drug: Desmopressin<br>* Sterile solution for injection<br>* Other names: MINIRIN® Injection;|
| Placebo Comparator: Placebo + desmopressin challenge dose<br>Subjects will receive a single subcutaneous dose of placebo followed by IV infusion (over 30 min of 0.3µg/kg desmopressin administered 24 hours after single dose of placebo | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>Drug: Desmopressin<br>* Sterile solution for injection<br>* Other names: MINIRIN® Injection;|
| Placebo Comparator: Placebo infusion<br>Subjects will receive a single IV dose of placebo administered over 24 hours | Drug: Placebo<br>* Sterile saline for injection<br>|
| Experimental: BT200 36.0mg<br>Subjects will receive a single subcutaneous (SC) dose of BT200 36.0mg by gradual SC infusion | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>|
| Experimental: BT200 48.0 mg<br>Subjects will receive a single subcutaneous dose (SC) of BT200 48.0mg by gradual SC infusion | Drug: BT200<br>* BT200 is a PEGylated synthetic RNA oligonucleotide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 |  | Baseline through 8 weeks after dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measured concentration of BT200 at serial time points |  | Baseline through 8 weeks after dosing | 
| Measured Area Under the Curve (AUC) |  | Baseline through 8 weeks after dosing | 
| Maximum Plasma Concentration (Cmax) |  | Baseline through 8 weeks after dosing | 
| Time to maximum plasma concentration (Tmax) |  | Baseline through 8 weeks after dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Secondary Stroke Prevention