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Trial registered on ANZCTR


Registration number
ACTRN12621000459820p
Ethics application status
Submitted, not yet approved
Date submitted
30/11/2020
Date registered
20/04/2021
Date last updated
20/04/2021
Date data sharing statement initially provided
20/04/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Relative Evaluation of the benefit of Cilnidipine ON the Nature, Observational Indices, Temperature changes, and overall Effect in secondary Raynaud’s disease (RECONNOITER-1)
Scientific title
A Randomized, Placebo-controlled Phase 2a Study to Assess the Safety and Efficacy of Cilnidipine (10 mg and 20 mg) Alone and in Combination with 5 mg Tadalafil, in Participants with Diagnosis of Secondary Raynaud’s Disease,
Secondary ID [1] 302621 0
None
Universal Trial Number (UTN)
U1111-1260-1080
Trial acronym
RECONNOITER-1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Raynaud's syndrome 319512 0
Condition category
Condition code
Cardiovascular 317469 317469 0 0
Other cardiovascular diseases
Inflammatory and Immune System 318680 318680 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Each participant will self-administer 1 tablet and 1 capsule daily for 12 consecutive days. Depending on which arm the participants get randomised, they will receive either 10 mg or 20 mg Cilnidipine tablet or placebo tablet and 5 mg of Tadalafil capsule or placebo capsule.
Intervention code [1] 318901 0
Treatment: Drugs
Comparator / control treatment
The placebo glucose tablet matches the study drug in weight and appearance and do not contain the active ingredient of the study drug.
Control group
Placebo

Outcomes
Primary outcome [1] 325499 0
Percentage change from baseline in frequency of Raynaud's Phenomenon (RP) attacks. Participants record RP attacks in the e-diary and this will be assessed daily by the researcher.

Timepoint [1] 325499 0
Primary Outcome will be percentage change from baseline in frequency of weekly RP attacks.
This are self-recorded by the participants in the e-diary. This will be reviewed daily by the researchers, and analysed weekly for percentage change in the frequency of the attack.
Secondary outcome [1] 388176 0
Change from Baseline in average duration of weekly RP attacks. This will be self recorded by the participant in the e-diary
Timepoint [1] 388176 0
The RP attacks will be assessed weekly.
Participants will be followed for 7 days following completion of the final Dosing period
Secondary outcome [2] 388177 0
Change from Baseline in average severity of weekly RP attacks. Severity is self marked by the participant as mild, moderate and severe using 11-point Likert scale.
Timepoint [2] 388177 0
The attacks are measured daily and recorded in the e-Diary and it is assessed by the researcher every day and analysed weekly.
Secondary outcome [3] 388178 0
Change from Baseline in average daily RCS.
The participant will be able to measure RCS score
Timepoint [3] 388178 0
This are self-recorded by the participants in the e-diary. This will be reviewed daily by the researchers, and analysed weekly for percentage change in the frequency of the attack.
Secondary outcome [4] 388179 0
Participants will be educated to use VAS. The outcome will be assessment of digital ulcer severity.
Timepoint [4] 388179 0
This are self-recorded by the participants in the e-diary. This will be reviewed daily by the researchers, and analysed for percentage change in the assessments (which will be conducted at Day 0 and Day 12)
Secondary outcome [5] 389292 0
Change from baseline in average pain score recorded during weekly RP attacks, as measured using a visual analogue scale (VAS)'
Timepoint [5] 389292 0
This are self-recorded by the participants in the e-diary. This will be reviewed daily from Day1 by the researchers, and analysed weekly for percentage change in the assessments up to 7 days from the last day of treatment
Secondary outcome [6] 389384 0
Change from baseline in net digital ulcer burden.
This are self-recorded by the participants in the e-diary. This will be reviewed daily from Day1 by the researchers, and analysed weekly for percentage change in the assessments up to 7 days from the last day of treatment
Timepoint [6] 389384 0
This are self-recorded by the participants in the e-diary. This will be reviewed daily from Day1 by the researchers, and analysed weekly for percentage change in the assessments up to 7 days from the last day of treatment
Secondary outcome [7] 389386 0
Change from baseline in participant quality of life measured using the Scleroderma Health Assessment Questionnaire (SHAQ)
Timepoint [7] 389386 0
This will occur at day 0 and day 12
Secondary outcome [8] 389387 0
The relevant metrics measured by an e-diary tool assess the severity of the attack -considering all symptoms of each attack (e.g. tingling, numbness, pain, colour changes)
Timepoint [8] 389387 0
This will be reviewed daily from Day1 by the researchers, and analysed weekly for percentage change in the assessments up to 7 days from the last day of treatment
Secondary outcome [9] 389388 0
Concomitant medication review will be assessed via consultation with the participant and review of medication charts and histories in the participants medial file,
Timepoint [9] 389388 0
This will be reviewed at an in-person clinic at Day 0, then self-recorded by the participants in the e-diary. daily from Day1-11 (reviewed electronically by the researchers), A final review will occur at an in-person clinic at day 12
Secondary outcome [10] 389389 0
One 4 mL blood sample will be obtained during each in-clinic visit within 2 to 6 hours of last dose of study drug in that Dosing Period as delineated in the Schedule of Assessment. The level of cilnidipine in blood will be measured following last dose of the Dosing Period
Timepoint [10] 389389 0
This is collected on Day 0 and 2-6 hours following final dose of each dosing period
Secondary outcome [11] 389393 0
Adverse events will be measured through out the study period from enrolment.
Vital signs are collected on Day 0 and During clinic visit after the last dose of the dosing period
Timepoint [11] 389393 0
daily for duration of study involvement (recorded in e-diary)
Secondary outcome [12] 393604 0
Raynaud's functional assessment will be conducted via digital examination by a physician delegated to the trial.
Timepoint [12] 393604 0
This will occur at day 0 and day 12
Secondary outcome [13] 393605 0
A pregnancy test for female participants of childbearing potential will be assessed using a urine sample
Timepoint [13] 393605 0
This will occur at day 0 and day 12
Secondary outcome [14] 393606 0
Thermography tests will be conducted on the most severely impacted digits (identified in screening) by a delegated trial nurses - and the results reviewed by the delegated trial physician
Timepoint [14] 393606 0
This will occur at Day 0 and day 12
Secondary outcome [15] 393608 0
Assessments for endothelial dysfunction will be performed using Endo-PAT with the results reviewed by a delegated physician
Timepoint [15] 393608 0
This will occur at Day 0 and day 12
Secondary outcome [16] 394163 0
Pharmacokinetic (PK) parameters will measure the level of cilnidipine in blood following last dose of each Dosing Period. All samples will be collected according to the PK sample manual, stored at -80 degree Celsius, shipped to and assessed by the central laboratory (Tetra Q, located in QLD).
Timepoint [16] 394163 0
PK samples will be collected at Day 0 and Day 12 of each Dosing period.

Eligibility
Key inclusion criteria
Participants at least 18 years of age diagnosed with severe secondary Raynaud’s disease (Raynaud’s Condition Score [RCS] greater than or equal to 40 and at least a 2-phase color change in fingers of pallor, cyanosis, and/or reactive hypermedia in response to cold exposure or emotion) mostly resulting from SSc and exhibiting regular and frequent RP attacks (averaging at least one attack per day) during the Screening period.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. A participant who meets any of the following exclusion criteria must be excluded from the study:
1. Primary Raynaud’s disease.
2. History of Raynaud’s attacks of sufficient severity as to require in-patient hospitalization (within the last 6 months).
3. The SBP of < 95 mm Hg during Randomization visit (Day 0).
4. Pulmonary hypertension requiring specific therapy for this condition.
5. Participants with an allergy to dihydropyridine CCBs that results in clinical findings such as profound hypotension, hives, rash, urticaria, wheezing and changes in breathing (Common treatment limiting adverse events [AEs] that occur with CCBs nifedipine and amlodipine such as edema, headache, heart rate changes, tachycardia, fatigue, constipation, flushing, drowsiness, dizziness should not limit enrollment into this study).
6. History of other chronic pain condition that could confound recording of pain scores during the study period.
7. Any prior or ongoing medical conditions, medical history, physical findings, or laboratory abnormality that in the opinion of the Investigator(s), would contraindicate administration of the study medication, or interfere with the study evaluations, or interfere with the participants ability to comply with the study protocol.
8. Cognitive or language difficulties that would impair completion of the study assessments.
9. Use of any investigational product (IP) or investigational medical device or participation in investigational drug studies within 30 days prior to enrollment in the study.
10. Those receiving nitrates, alpha blockers, PDE inhibitors (outside of stable administration for PAH), prostacyclins or endothelin antagonists.
11. History of orthostatic hypertension, dizziness or fainting spells, acute coronary or cerebrovascular event within 3 months of study enrollment.
12. History of major thoracic, abdominal, or vascular surgery within 6 months of study enrollment; History of sympathectomy.
13. Severe cardiomyopathy, severe valvular heart disease, chronic kidney disease (CKD) stage 3 or greater, evidence of malignancy, end stage lung disease.
14. Pregnant or lactating women.
15. Women of childbearing potential (WOCBP) unable to comply with contraceptive requirements during the study period.
16. Males with partners who are WOCBP and are unable to comply with the contraceptive requirements during the study.
17. History of drug or excess alcohol use that in the opinion of the Investigator(s) would affect the participant’s ability to reliably participate in the study. NHMRC guidelines for regular alcohol consumption in healthy adults are no more than 10 standard drinks per week and no more than four standard drinks on any one day.
18. Use of tobacco products of any type in the preceding one month and for the duration of the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participant will be randomized into different treatment by using a statistical software package through a computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Participant disposition will be analyzed using counts and percentages. The number and percentage of screened participants, enrolled participants, treated participants, participants discontinued from the study and study treatment, as well as the primary reason for discontinuation will be analyzed and listed.

Participant demography and baseline characteristics data will be summarized using descriptive statistics. The following demographic variables will be summarized by dose level: race, gender, age, height and weight, concomitant diseases (Hypertension, peripheral vascular disease, diabetes, CKD and stage, osteoporosis, history and type of heart arrhythmia).

In addition, the following baseline characteristics of Raynauds Disease will be summarized: age of onset, seasonality (months disease is worst), usual number of attacks/day, usual peak severity, baseline RCS assessment, how attacks are usually treated, how long attacks last in general, experience with other treatments both pharmacological and non-pharmacological.

Medical history terms will be coded using the MedDRA® Version 22.0 or higher. Medical history will be analyzed using descriptive statistics by MedDRA® SOC and PT.
Prior and concomitant medications will be coded using the most current version of the WHO drug dictionary available at the start of the study. Prior and concomitant medications will be listed by participant and summarized by treatment using anatomical therapeutic chemical (ATC) and preferred name.

Treatment compliance and exposure will be summarized and listed by treatment for all participants in the Safety population.

Analysis of Primary Endpoint - Percent change from baseline evaluation for frequency of weekly RP attacks will be the primary efficacy endpoint. Data collected in the last 7 days of each Dosing Period will be used for this analysis. Screening assessments will be used as baseline for the analysis of all periods. No multiple comparison adjustment will be used to control alpha for the multiple comparisons. Mixed effects model will be used for analysis of the primary endpoint according to the crossover design. Other efficacy endpoints of continuous variables will be analyzed using similar methodology. For nominal data, Chi-square tests will be applied. Generalized Estimating Equations method will be used, as appropriate, for adjusting for potential confounding factors. In addition, the final analysis will assess whether in this study of severe Raynaud’s disease participants, the minimally important difference, previously concluded of 14-15 points on the 100 point RCS scale (Khanna, 2010) has been achieved in the cilnidipine dose group. It also will record the percentage of participants achieving a PASS (34 point difference from baseline on a 0-100 VAS) (Khanna, 2010) in each treatment group.

The secondary endpoints of change from baseline evaluation will be compared among treatment groups using mixed effects model. Kaplan-Meier method will be used to evaluate time to event endpoints. To evaluate the impact of daily ambient temperature on symptomatic Raynaud’s attack, logistic regression will be used for temperature versus the occurrence of Raynaud’s attack (Yes/No). The effect of temperature on the severity score of Raynaud’s attacks and difference of using rescue medication between treatment groups will be evaluated by Chi-square test. The impact of therapy in sympathetic activity will be assessed by mixed model for repeated measures.

All safety assessments, including AEs, laboratory evaluations, vital signs, and other safety assessments will be analyzed using the Safety population.

Adverse events will be coded using the most current version of the MedDRA® Version 22.0 or higher. The analysis of AEs will be based on the concept of treatment emergent AEs. Treatment emergent AEs will be tabulated by treatment group and will include the number of participants for whom the event occurred, the severity, and relationship to study drug. Treatment emergent AEs (TEAEs) leading to discontinuation and SAEs with onset after the start of study drug will also be summarized.
All AEs and SAEs (including those with onset or worsening before the start of study drug) through the end of the study will be listed.

Baseline laboratory evaluations will be listed and summarized by treatment.

Vital signs (BP [systolic and diastolic], pulse rate, and oral temperature) will be listed and summarized by treatment and protocol specified collection time point. Observed and change from baseline will be summarized at each protocol specified collection time point.

Other Safety Assessments
The following assessments will be listed by participant:
• Pregnancy Test
• Raynaud’s function assessment by physician.

Pharmacokinetics
Plasma concentrations and actual blood sampling times will be listed by treatment and protocol specified time point and summarized using descriptive statistics — number of measurements, arithmetic mean, SD, and %CV, geometric mean, minimum, median, and maximum – at each scheduled time point. Individual and mean plasma concentration-time profiles will also be presented graphically for each treatment.
Pharmacokinetic parameters will be computed from the individual plasma concentrations using a non-compartmental approach.
Value for elimination rate constant (kel), elimination half-life (t½), Area under the plasma concentration-time curve from time zero to infinity (AUC0-inf), apparent total clearance of the drug from plasma after oral administration (CL/F) or apparent volume of distribution during terminal phase after non-intravenous administration (Vz/F) will not be reported. Additional analyses will be performed as deemed necessary upon review of the data.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 18125 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [2] 18126 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 32118 0
5042 - Bedford Park
Recruitment postcode(s) [2] 32119 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 307051 0
Commercial sector/Industry
Name [1] 307051 0
AISA Pharma Australia Pty. Ltd.
Address [1] 307051 0
AISA Pharma Australia Pty Ltd
9 Adelaide Ave, East Lindfield 2070
Sydney, NSW, Australia
Country [1] 307051 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
AISA Pharma Australia Pty. Ltd.
Address
AISA Pharma Australia Pty Ltd
9 Adelaide Ave, East Lindfield 2070
Sydney, NSW, Australia
Country
Australia
Secondary sponsor category [1] 307616 0
None
Name [1] 307616 0
Address [1] 307616 0
Country [1] 307616 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 307175 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 307175 0
c/- Flinders Medical Centre
1 Flinders Drive
BEDFORD PARK SA 5042
Ethics committee country [1] 307175 0
Australia
Date submitted for ethics approval [1] 307175 0
18/01/2021
Approval date [1] 307175 0
Ethics approval number [1] 307175 0

Summary
Brief summary
A randomized, placebo-controlled Phase 2a study to test the efficacy and safety of cilnidipine alone and in combination with tadalafil in participants at least 18 years of age diagnosed with severe secondary Raynaud’s disease (Raynaud’s Condition Score [RCS]
greater than o r equal 40 and at least a 2-phase colour change in fingers of pallor, cyanosis, and/or reactive hypermedia in response to cold exposure or emotion) mostly resulting from SSc and exhibiting regular and frequent RP attacks (averaging at least one attack per day) during the Screening period.
Double-blind, Placebo-controlled, Parallel-group, Dose Selection to assess the safety and efficacy of two doses of cilnidipine (10 mg and 20 mg), alone and in combination with tadalafil. Participants will be randomized to one of six prespecified treatment arms.
During the study 36 participants will receive treatments in a blinded fashion. Placebo tablets (matching cilnidipine) and placebo capsules (matching tadalafil), for oral administration, will be provided to the site as well as the investigational treatments (cilnidipine and tadalafil). Medications will be dispensed during the preceding in-clinic study visit for self-administration by the participant.
Each Dosing Period will last for 12 days (allowing for a variance window of -2 days [d10] or +2 days [d14] ) in which participants will take daily doses of assigned treatment in the morning. For each day of dosing, participants will take one capsule and one tablet to blind the active therapy being received. Dropouts will not be replaced.
Primary Efficacy Endpoint: Percentage change from baseline in frequency of weekly RP attacks.
Safety Endpoints: Incidence of adverse events (AEs) and serious adverse events (SAEs), including clinically significant vital signs from the time of randomization until 7 days following the last protocol dose.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106298 0
Prof Michael Shanahan
Address 106298 0
Flinders University
Sturt Road
BEDFORD PARK SA 5042
Country 106298 0
Australia
Phone 106298 0
+61 8 8275 1819
Fax 106298 0
Email 106298 0
michael.shanahan@flinders.edu.au
Contact person for public queries
Name 106299 0
Dr Erin Morton
Address 106299 0
Flinders University
Sturt Road
BEDFORD PARK SA 5042
Country 106299 0
Australia
Phone 106299 0
+61 8 8204 5836
Fax 106299 0
Email 106299 0
erin.morton@flinders.edu.au
Contact person for scientific queries
Name 106300 0
Ms Meredith Todd
Address 106300 0
AISA Pharma Australia Pty Ltd
9 Adelaide Ave, East Lindfield 2070
Sydney, NSW, Australia
Mobile: 0432-663-121
Country 106300 0
Australia
Phone 106300 0
+61432 663 121
Fax 106300 0
Email 106300 0
mtodd@aisapharm.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results