Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000999437
Ethics application status
Approved
Date submitted
25/08/2025
Date registered
9/09/2025
Date last updated
9/09/2025
Date data sharing statement initially provided
9/09/2025
Type of registration
Retrospectively 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): Part B
Scientific title
A Randomized, Double-blind, 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, also Referred to as Reconnoiter-1: Randomized Evaluation of the Benefit of Cilnidipine Dose on the Nature, Observational Indices, Temperature Changes, and Overall Effect in Secondary Raynaud’s Disease (Part B: Cilnidipine alone)
Secondary ID [1] 315225 0
None
Universal Trial Number (UTN)
Trial acronym
RECONNOITER-1
Linked study record
This record pertains to RECONNOITER-1 Part B, which follows ACTRN12621000459820 (RECONNOITER-1 Part A)

Health condition
Health condition(s) or problem(s) studied:
Raynaud's Syndrome 338675 0
Condition category
Condition code
Cardiovascular 334965 334965 0 0
Other cardiovascular diseases
Inflammatory and Immune System 334966 334966 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Cilnidipine (20mg) oral tablet once daily for 12 ± 2 days, with a 4 (± 1) day washout period between dosing periods in the crossover design.
Exact duration within these windows is on a case-by-case basis considering both physician and participant availability.
Medication usage is recorded in a daily diary and any unused doses returned at the conclusion of the dosing period.
Intervention code [1] 331837 0
Treatment: Drugs
Comparator / control treatment
Matching placebo (visually matching predominantly cellulose/lactose) oral tablet once daily for 12 ± 2 days, with a 4 (± 1) day washout period between dosing periods in the crossover design.
Exact duration within these windows is on a case-by-case basis considering both physician and participant availability.
Medication usage is recorded in a daily diary and any unused doses returned at the conclusion of the dosing period.
Control group
Placebo

Outcomes
Primary outcome [1] 342596 0
Frequency of weekly Raynaud’s Phenomenon (RP) attacks (percentage change from baseline, relative to placebo)
Timepoint [1] 342596 0
Attacks are recorded in a daily participant diary for duration of study participation, and frequency calculated and analysed for each dosing period (12 ± 2 days).
Secondary outcome [1] 451456 0
Severity of Raynaud's Phenomenon (RP) attacks (percentage change from baseline, relative to placebo)
Timepoint [1] 451456 0
Attacks are recorded in a daily participant diary for duration of study participation, and severity calculated and analysed for each dosing period (12 ± 2 days).
Secondary outcome [2] 451457 0
Duration of Raynaud's Phenomenon (RP) attacks (percentage change from baseline, relative to placebo)
Timepoint [2] 451457 0
Attacks are recorded in a daily participant diary for duration of study participation, and duration calculated and analysed for each dosing period (12 ± 2 days).
Secondary outcome [3] 451458 0
Change from baseline in average daily Raynaud's Condition Score (RCS)
Timepoint [3] 451458 0
Scores are recorded in a daily participant diary for duration of study participation, and average scores calculated and analysed for each dosing period (12 ± 2 days).
Secondary outcome [4] 451459 0
Change from baseline in highest (most severe) pain score recorded during weekly RP attacks.
Timepoint [4] 451459 0
Scores are recorded in a daily participant diary for duration of study participation, and highest scores calculated and analysed for each dosing period (12 ± 2 days).
Secondary outcome [5] 451460 0
Change from baseline in average pain score recorded during weekly RP attacks
Timepoint [5] 451460 0
Scores are recorded in a daily participant diary for duration of study participation, and average scores calculated and analysed for each dosing period (12 ± 2 days).
Secondary outcome [6] 451461 0
Change from baseline in net digital ulcer burden
Timepoint [6] 451461 0
Assessed by physician or designee at baseline and the end of each dosing period (12 ± 2 days)
Secondary outcome [7] 451462 0
Change from baseline in distal-dorsal difference (DDD) of the affected index finger sites
Timepoint [7] 451462 0
Assessed at baseline and the end of each dosing period (12 ± 2 days)
Secondary outcome [8] 451463 0
Change from baseline in participant quality of life and other aspects of scleroderma disease
Timepoint [8] 451463 0
Completed at baseline and at the end of each dosing period (12 ± 2 days)
Secondary outcome [9] 451464 0
Change from baseline in participant gastrointestinal symptoms (of sclerosis)
Timepoint [9] 451464 0
Assessed at baseline and the end of each dosing period (12 ± 2 days)
Secondary outcome [10] 451465 0
Change from baseline in Raynaud-VAS
Timepoint [10] 451465 0
Assessed at baseline and the end of each dosing period (12 ± 2 days)
Secondary outcome [11] 451466 0
Change from baseline in physician assessment of disease
Timepoint [11] 451466 0
Assessed at baseline and the end of each dosing period (12 ± 2 days)
Secondary outcome [12] 451467 0
Cilnidipine drug levels taken 2 to 6 hours following the last dose
Timepoint [12] 451467 0
Single blood sample is taken at the end of each dosing period (12 ± 2 days), within 2 to 6 hours of last dose of study drug in that Dosing Period.
Secondary outcome [13] 451468 0
Time to reach maximum degree of efficacy (in days) compared to baseline
Timepoint [13] 451468 0
Attacks are recorded in a daily participant diary for duration of study participation, and frequency calculated and analysed for each dosing period (12 ± 2 days).
Secondary outcome [14] 451469 0
Time to return to baseline symptom severity after termination of dosing
Timepoint [14] 451469 0
Attacks are recorded in a daily participant diary for duration of study participation (2 x 12 ± 2 days dosing periods, plus 7 days after final dose), and severity calculated and analysed for 7 days after completion of each dosing period.
Secondary outcome [15] 451470 0
Use of rescue medications for breakthrough symptoms
Timepoint [15] 451470 0
Medication use is recorded in a daily participant diary for duration of study participation, and and analysed for each dosing period (12 ± 2 days)
Secondary outcome [16] 451471 0
Incidence of treatment emergent AEs and SAEs, including clinically significant vital signs (significant reduction in blood pressure compared to baseline or SBP less than 90 mmHg), orthostatic dizziness, or any symptoms of possible allergic phenomena.
Timepoint [16] 451471 0
Duration of trial participation (2 x 12 ± 2 days), plus self-reported events at safety follow-up 7 and 28-days post-dosing)
Secondary outcome [17] 451472 0
Exploratory outcome: Change from baseline in endothelial function as measured by reactive hyperemia index (RHI)
Timepoint [17] 451472 0
At baseline and end of each dosing period (12 ± 2 days)
Secondary outcome [18] 451473 0
Exploratory outcome: Change from baseline in novel patient-reported outcomes (ASRAP score) which assesses the severity and impact of Raynaud's Phenomenon in Systemic Sclerosis
Timepoint [18] 451473 0
At baseline and at the end of each dosing period (12 ± 2 days)
Secondary outcome [19] 451474 0
Exploratory Outcome: Change from baseline in combination endpoint (frequency of weekly RP attacks and ASRAP score)
Timepoint [19] 451474 0
Score calculated at the end of each dosing period (12 ± 2 days)
Secondary outcome [20] 451475 0
Exploratory Outcome: Change from baseline in reported ocular symptoms
Timepoint [20] 451475 0
At baseline and the end of each dosing period (12 ± 2 days)

Eligibility
Key inclusion criteria
- Severe secondary Raynaud’s disease (with patient reported RCS at baseline of at least 20) based on ACR criteria mostly resulting from SSc.
- Regular and frequent Raynaud’s attacks (averaging at least one attack per day) during the Screening week (in participants with at least a 2-phase color change in fingers of pallor, cyanosis, and/or reactive hyperemia in response to cold exposure or emotion).
- Willingness to complete the daily diary entry’s during the Screening period.
- Participants must be willing and able to provide written informed consent after the nature of the study has been explained and prior to the commencement of any study procedures.
- Willingness to forego therapies for Raynaud’s during study participation is preferred (except for selective serotonin reuptake inhibitors such as fluoxetine which should not be discontinued) Ongoing treatment with CCBs and other routine therapies for SSc-RP is permitted however, if it is not clinically feasible to stop therapy, the participant has been on a stable dose for the last 2 months and meets all eligibility criteria. Rescue therapy (with acetaminophen, nonsteroidal anti-inflammatory drug [NSAIDs], other codeine analgesics, fluoxetine, angiotensin II receptor blockers (ARBs) such as losartan) or CCBs will be allowed to manage breakthrough symptoms of SSc-RP but must be documented).
- Participants who are on a stable dose (no change in the last 2 months) of a CCB for hypertension or PDE5 inhibitors for pulmonary hypertension may continue these agents at this stable dose as long as they meet other inclusion criteria during Screening.
- Have agreed not to use (or initiate treatment with) other investigational therapies or unapproved therapies during the course of the study outside of protocol allowances for rescue medication (such medications include but are not limited to: nitroglycerin, topical creams, fenoldopam, nimodipine, amlodipine, fluoxetine, pregabalin, gabapentin, verapamil, sildenafil, tadalafil, vardenafil).
- Women of childbearing potential (WOCBP) who have agreed to use an effective method of contraception during the study and for 30 days after the last study dose. Acceptable methods of birth control in this study include oral contraceptive, barrier control, or implanted devices. A woman must agree not to donate eggs (ova; oocytes) for purposes of reproduction for at least 30 days after last dose of study drug.
- Post-menopausal females, aged over 45 years who have not had a period for at least 12 months, and are not using hormonal contraception, or females documented as permanently sterile (e.g., bilateral tubal ligation; hysterectomy, bilateral salpingectomy).
- Negative urine pregnancy test on Randomization day (WOCBP only).
- All sexually active men whose partner is a WOCBP (due to potential risk of drug exposure through the ejaculate) who agree to a barrier method of birth control during the study and for 30 days after the last dose of the study drug. All men must agree not to donate sperm for at least 30 days after receiving last dose of study drug.
- Participants must have clinical laboratory values within normal range as specified by the testing laboratory at their most recent pre-screening sample, unless deemed not clinically significant by the Investigator or delegate. Lab sample may be within the last 2 months as long as there have been no significant clinical changes since the last labs and no new medications (e.g. Diuretics) have been introduced that are known to be associated with changes in clinical chemistry or hematology values (e.g. potassium with diuretics or cyclosporine associated with aplastic anemia).
Minimum age
18 Years
Maximum age
90 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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. SBP of < 95 mm Hg during Randomization visit (Day 0).
4. 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 enrolment into this study).
5. History of other chronic pain condition that could confound recording of pain scores during the study period.
6. 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.
7. Cognitive or language difficulties that would impair completion of the study assessments.
8. Use of any investigational product (IP) or investigational medical device or participation in investigational drug studies within 30 days prior to enrolment in the study.
9. Those receiving nitrates (nitro-dur, nitroglycerin) or similar agents that have vasodilatory effects (eg. nicorandil) prescribed to treat angina, alpha blockers, PDE inhibitors, prostacyclins or endothelin antagonists for whom dose is not stable for > 2 months
10. History of orthostatic hypotension, dizziness or fainting spells, acute coronary or cerebrovascular event within 3 months of study enrolment.
11. History of major thoracic, abdominal, or vascular surgery within 6 months of study enrolment; History of sympathectomy in the hand which is symptomatic for RP.
12. Severe cardiomyopathy, severe valvular heart disease, chronic kidney disease (CKD) stage 3 or greater, evidence of malignancy, end stage lung disease.
13. Pregnant or lactating women.
14. Women of childbearing potential (WOCBP) unable to comply with contraceptive requirements during the study period.
15. Males with partners who are WOCBP and are unable to comply with the contraceptive requirements during the study.
16. History of drug (including recreational use of inhaled amyl nitrates or party poppers) 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.
17. Heavy smokers of tobacco products of any type (defined as >10 cigarettes per day). Light smokers who agree to keep their smoking stable for the duration of their trial participation are eligible.

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)
Allocation will be revealed after completion of the study for all participants.
Study medication and placebo are distributed to sites in matched packaging.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A block randomization list will be prepared using a statistical software package by a Biostatistician who is independent of the trial conduct.
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
Crossover
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
31/03/2023
Date of last participant enrolment
Anticipated
31/10/2025
Actual
Date of last data collection
Anticipated
31/12/2025
Actual
Sample size
Target
38
Accrual to date
32
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 28385 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 44606 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 319791 0
Commercial sector/Industry
Name [1] 319791 0
AISA Pharma Australia Pty. Ltd.
Country [1] 319791 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
AISA Pharma Australia Pty. Ltd.
Address
Country
Australia
Secondary sponsor category [1] 322306 0
None
Name [1] 322306 0
Address [1] 322306 0
Country [1] 322306 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 318350 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 318350 0
Ethics committee country [1] 318350 0
Australia
Date submitted for ethics approval [1] 318350 0
18/01/2021
Approval date [1] 318350 0
22/04/2021
Ethics approval number [1] 318350 0
2021/HRE00011

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 143898 0
Prof Michael Shanahan
Address 143898 0
Flinders University Sturt Road BEDFORD PARK SA 5042
Country 143898 0
Australia
Phone 143898 0
+61 8 8275 1819
Fax 143898 0
Email 143898 0
[email protected]
Contact person for public queries
Name 143899 0
Kelly Loffler
Address 143899 0
Flinders University Sturt Road BEDFORD PARK SA 5042
Country 143899 0
Australia
Phone 143899 0
+61 468566663
Fax 143899 0
Email 143899 0
[email protected]
Contact person for scientific queries
Name 143900 0
Meredith Todd
Address 143900 0
AISA Pharma Australia Pty Ltd 9 Adelaide Ave, East Lindfield 2070 Sydney, NSW, Australia
Country 143900 0
Australia
Phone 143900 0
+61 432 663 121
Fax 143900 0
Email 143900 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.