A Study to Assess the Effect of Oral Temanogrel on Digital Blood Flow in Adult Participants With Raynaud's Phenomenon Secondary to Systemic Sclerosis

Study Overview
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Brief Summary
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The purpose of this study is to determine whether oral temanogrel improves digital blood flow in participants with Raynaud's phenomenon secondary to systemic sclerosis (SSc-RP) as a potential safe and effective treatment for symptoms associated with SSc-RP.

Detailed Description
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The study will be conducted in 2 stages: Stage A and Stage B. In both stages, participants will be equally randomized in a double-blind manner to a 3-period crossover treatment sequence. Separate cohorts of participants will participate in each stage. In Stage A, participants will be treated with two dose levels of temanogrel and placebo. Doses in Stage B will be determined based on the results of Stage A.

Official Title
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A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Assess the Effect of Oral Temanogrel on Digital Blood Flow in Subjects With Raynaud's Phenomenon Secondary to Systemic Sclerosis

Conditions
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Raynaud's Phenomenon Secondary to Systemic Sclerosis

Intervention / Treatment
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* Drug: Temanogrel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Raynaud's phenomenon (defined as a history of digital cold sensitivity associated with color changes of cyanosis and pallor, with on average at least 5 attacks per week during the winter period) secondary to systemic sclerosis (SSc) Both men and women participants agree to use a highly effective method of birth control if the possibility of conception exists Body mass index 18.0 to 40.0 kilograms per square meter (kg/m^2), inclusive Exclusion Criteria: Active digital ulcer(s), recent history (within 3 months of Screening) of digital ulcers, or history of recurrent digital ulcerations that in the opinion of the Investigator increase the likelihood of developing a digital ulcer during the course of the study. Any history of gangrene, amputations, or other critical digital ischemic event Raynaud's phenomenon due to any cause other than SSc Severe gastrointestinal complications related to SSc that in the opinion of the Investigator could significantly affect study drug absorption History of gastrointestinal bleeding or active gastric or duodenal ulcers

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Temanogrel (Stage A Dose 1)<br> | Drug: Temanogrel<br>* Participants will receive a single oral dose of temanogrel during the treatment visit.<br>* Other names: APD791;|
| Experimental: Temanogrel (Stage A Dose 2)<br> | Drug: Temanogrel<br>* Participants will receive a single oral dose of temanogrel during the treatment visit.<br>* Other names: APD791;|
| Placebo Comparator: Placebo (Stage A)<br> | Drug: Placebo<br>* Participants will receive a single oral dose of temanogrel matching placebo during the treatment visit.<br>|
| Experimental: Temanogrel (Stage B Dose 1)<br> | Drug: Temanogrel<br>* Participants will receive a single oral dose of temanogrel during the treatment visit.<br>* Other names: APD791;|
| Experimental: Temanogrel (Stage B Dose 2)<br> | Drug: Temanogrel<br>* Participants will receive a single oral dose of temanogrel during the treatment visit.<br>* Other names: APD791;|
| Placebo Comparator: Placebo (Stage B)<br> | Drug: Placebo<br>* Participants will receive a single oral dose of temanogrel matching placebo during the treatment visit.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Digital Blood Flow Based on Rewarming Area Under the Curve (AUC) During Thirty Minutes Following a Cold Challenge | Area under the curve for rewarming of digital blood flow after 30 minutes following a cold challenge was assessed. Area under the curve was defined as the area under the skin temperature curve and rewarming was a delicate phase of therapeutic hypothermia (TH). A cold challenge was conducted by immersing the hands in a temperature-controlled water bath (15 [+/- 1] degree celsius) for one minute, followed by post-cold challenge digital blood flow assessments for 30 minutes. Rewarming was assessed by infrared (IR) thermography which was an indirect method for evaluation of blood flow based on imaging skin temperature. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | 30 minutes following a cold challenge | 
| Change in Digital Blood Flow Based on Reperfusion AUC During the Thirty Minutes Following a Cold Challenge | Area under the curve for reperfusion of digital blood flow after 30 minutes following a cold challenge was assessed. A cold challenge was conducted by immersing hands in a temperature-controlled water bath (15 [+/- 1] degree celsius) for one minute, followed by post-cold challenge digital blood flow assessments for 30 minutes. Reperfusion was assessed with laser speckle contrast imaging (LSCI) which was based on differences in the speckle pattern (occurring when laser light illuminates a tissue) due to movement of blood cells. LSCI therefore provides quantitative measures of blood flow within predefined region of interests (ROIs) as mean arbitrary perfusion units, pu. Higher values of pu (and also pu*seconds) are considered better in the context of this trial. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | 30 minutes following a cold challenge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Reduction in Temperature Following a Cold Challenge Assessed With Infrared (IR) Thermography | IR thermography was an indirect method for evaluation of blood flow based on imaging skin temperature. A cold challenge was conducted by immersing the hands in a temperature-controlled water bath (15 [+/- 1] degree celsius) for one minute, followed by post-cold challenge digital blood flow assessments for 30 minutes. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | 30 minutes following a cold challenge | 
| Maximum Reduction in Perfusion Temperature Following a Cold Challenge With Laser Speckle Contrast Imaging (LSCI) | A cold challenge was conducted by immersing the hands in a temperature-controlled water bath (15 [+/- 1] degree celsius) for one minute, followed by post-cold challenge digital blood flow assessments for 30 minutes. LSCI was based on differences in the speckle pattern (occurring when laser light illuminates a tissue) due to movement of blood cells. LSCI therefore provides quantitative measures of blood flow within predefined region of interests (ROIs) as mean arbitrary perfusion units, pu. Higher values of pu are considered better in the context of this trial. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | 30 minutes following a cold challenge | 
| Maximum Recovery in Temperature Following a Cold Challenge Assessed With IR Thermography | IR thermography was an indirect method for evaluation of blood flow based on imaging skin temperature. Changes in skin temperature at each visit were imaged IR thermography. A cold challenge was conducted by immersing the hands in a temperature-controlled water bath (15 [+/- 1] degree celsius) for one minute, followed by post-cold challenge digital blood flow assessments for 30 minutes. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | 30 minutes following a cold challenge | 
| Maximum Recovery in Perfusion Temperature Following a Cold Challenge Assessed With LSCI | A cold challenge was conducted by immersing the hands in a temperature-controlled water bath (15 [+/- 1] degree celsius) for one minute, followed by post-cold challenge digital blood flow assessments for 30 minutes. LSCI was based on differences in the speckle pattern (occurring when laser light illuminates a tissue) due to movement of blood cells. Changes in skin temperature at each visit were imaged using LSCI. LSCI therefore provides quantitative measures of blood flow within predefined region of interests (ROIs) as mean arbitrary perfusion units, pu. Higher values of pu are considered better in the context of this trial. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | 30 minutes following a cold challenge | 
| AUC During the Initial Two Minutes Following a Cold Challenge Assessed With IR Thermography | AUC was defined as the area under the skin temperature curve. IR thermography was an indirect method for evaluation of blood flow based on imaging skin temperature. A cold challenge was conducted by immersing the hands in a temperature-controlled water bath (15 [+/- 1] degree celsius) for one minute, followed by post-cold challenge digital blood flow assessments. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | Initial 2 minutes following a cold challenge | 
| Perfusion AUC During the Initial Two Minutes Following a Cold Challenge Assessed With LSCI | A cold challenge was conducted by immersing the hands in a temperature-controlled water bath (15 [+/- 1] degree celsius) for one minute, followed by post-cold challenge digital blood flow assessments. LSCI was based on differences in the speckle pattern (occurring when laser light illuminates a tissue) due to movement of blood cells. LSCI therefore provides quantitative measures of blood flow within predefined region of interests (ROIs) as mean arbitrary perfusion units, pu. Higher values of pu (and also pu*seconds) are considered better in the context of this trial. AUC was defined as the area under the skin temperature curve, based on the LSCI results. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | Initial 2 minutes following a cold challenge | 
| Slope During the Initial 2 Minutes (120 Seconds) Following a Cold Challenge Assessed With IR Thermography | IR thermography was an indirect method for evaluation of blood flow based on imaging skin temperature. A cold challenge was conducted by immersing the hands in a temperature-controlled water bath (15 [+/- 1] degree celsius) for 60 seconds, followed by post-cold challenge digital blood flow assessments. Slope was calculated based on the changes in skin temperature imaged using LSCI and IR thermography during the initial 120 seconds following the cold challenge. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | Initial 2 minutes following a cold challenge | 
| Perfusion Slope During the Initial 2 Minutes (120 Seconds) Following a Cold Challenge Assessed With LSCI | A cold challenge was conducted by immersing the hands in a temperature-controlled water bath (15 [+/- 1] degree celsius) for 60 seconds, followed by post-cold challenge digital blood flow assessments. LSCI was based on differences in the speckle pattern (occurring when laser light illuminates a tissue) due to movement of blood cells. LSCI therefore provides quantitative measures of blood flow within predefined region of interests (ROIs) as mean arbitrary perfusion units, pu. Higher values of pu (and also pu/seconds) are considered better in the context of this trial. Slope was calculated based on the changes in skin temperature imaged using LSCI during the initial 120 seconds following the cold challenge. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | Initial 2 minutes following a cold challenge | 
| Time to Achieve 50 Percent (%) Recovery From the Cold Challenge-Induced Reduction Assessed With IR Thermography and With LSCI | IR thermography was an indirect method for evaluation of blood flow based on imaging skin temperature, while LSCI was based on differences in the speckle pattern (occurring when laser light illuminates a tissue) due to movement of blood cells. A cold challenge was conducted by immersing the hands in a temperature-controlled water bath (15 [+/- 1] degree celsius) for one minute, followed by post-cold challenge digital blood flow assessments. If 50% recovery was not achieved, the recovery time was set to 30 minutes. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | 30 minutes following a cold challenge | 
| Time to Achieve 70 % Recovery From the Cold Challenge-Induced Reduction Assessed With IR Thermography and With LSCI | IR thermography was an indirect method for evaluation of blood flow based on imaging skin temperature, while LSCI was based on differences in the speckle pattern (occurring when laser light illuminates a tissue) due to movement of blood cells. A cold challenge was conducted by immersing the hands in a temperature-controlled water bath (15 [+/- 1] degree celsius) for one minute, followed by post-cold challenge digital blood flow assessments. If 70% recovery was not achieved, the recovery time was set to 30 minutes. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | 30 minutes following a cold challenge | 
| Change From Predose to Post-dose in Room Temperature Values as Assessed With IR Thermography | IR thermography was an indirect method for evaluation of blood flow based on imaging skin temperature. Digital blood flow was assessed at each treatment visit at Predose for 5 minutes at room temperature, and at post-dose prior to cold challenge for 5 minutes at room temperature. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | 5 minutes pre-dose, 5 minutes post-dose | 
| Change From Predose to Post-dose in Room Temperature Perfusion Values as Assessed With LSCI | Digital blood flow was assessed at each treatment visit at Predose for 5 minutes at room temperature, and at post-dose prior to cold challenge for 5 minutes at room temperature. LSCI was based on differences in the speckle pattern (occurring when laser light illuminates a tissue) due to movement of blood cells. LSCI therefore provides quantitative measures of blood flow within predefined region of interests (ROIs) as mean arbitrary perfusion units, pu. Higher values of pu are considered better in the context of this trial. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | 5 minutes pre-dose, 5 minutes post-dose | 
| Change From Predose to Post-dose in Distal Dorsal Difference (DDD), Assessed With IR Thermography | The distal dorsal difference was defined as the difference in temperature between the dorsum and the finger, from pre dose of study treatment to post-dose. IR thermography was an indirect method for evaluation of blood flow based on imaging skin temperature. Digital blood flow was assessed at each treatment visit at Predose for 5 minutes at room temperature, and at postdose prior to cold challenge for 5 minutes at room temperature. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | 5 minutes pre-dose, 5 minutes post-dose | 
| Change From Predose to Post-dose in Distal Dorsal Difference (DDD) [Perfusion], Assessed With LSCI | Digital blood flow was assessed at each treatment visit at Predose for 5 minutes at room temperature, and at postdose prior to cold challenge for 5 minutes at room temperature. LSCI was based on differences in the speckle pattern (occurring when laser light illuminates a tissue) due to movement of blood cells. LSCI therefore provides quantitative measures of blood flow within predefined region of interests (ROIs) as mean arbitrary perfusion units, pu. Higher values of pu are considered better in the context of this trial. The distal dorsal difference was defined as the difference in perfusion temperature between the dorsum and the finger, from pre dose of study treatment to post-dose. Results presented were based on the average across all 8 fingers assessed (left index, left middle, left ring, left little, right index, right middle, right ring, right little). | 5 minutes pre-dose, 5 minutes post-dose | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | An adverse event was any untoward medical occurrence that did not necessarily have a causal relationship with study treatment. TEAE was an AE that occurred after initiation of study treatment that was not present at the time of treatment start or an AE that increased in severity after the initiation of medication, if the event was present at the time of treatment start. SAE was an AE resulting in any of the following outcomes or considered medically significant: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or birth defect. | Day 1 of dose to maximum of 4 (+/-1) days after last dose (up to maximum of 22 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Raynaud's phenomenon, SSc-RP, Systemic sclerosis, SSc, Digital cold sensitivity, Digital blood flow, APD791, Temanogrel