Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202404895013782 Date of Approval: 23/04/2024
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title DM199 for Pregnancy Complications
Official scientific title DM199 for Pregnancy Complications
Brief summary describing the background and objectives of the trial Preeclampsia and fetal growth restriction are leading causes of maternal and fetal morbidity. Both result from poor placental function. Preeclampsia is further characterised by inflammation and oxidative stress, leading to maternal endothelial dysfunction and hypertension. Hence, a drug that improves maternal vascular function including vasodilatation (and blood pressure reduction) may be a treatment for both conditions. Tissue kallikrein (KLK1) is an endogenous enzyme that cleaves kininogen to produce active kinins, mainly bradykinin. Bradykinin is a potent natural vasodilator with pro-angiogenic and possible anti-oxidant and potentially anti-inflammatory effects. Specifically, bradykinin binds and activates the bradykinin 2 receptor located on blood vessel endothelium. Activation of these receptors increases nitric oxide and prostacyclin production, resulting in relaxation of the smooth muscle of blood vessels and consequently vasodilation. Bradykinin 2 receptor activation may also have other beneficial actions such as upregulating antioxidant defenses. DM199 is a pharmaceutical formulation comprised of recombinant tissue kallikrein. It is a protein that is identical to KLK1, except for two amnio acids. Given the beneficial actions of KLK1, DM199 could be a therapeutic to treat preeclampsia. Furthermore, its vasodilatory properties might enhance blood perfusion to the placenta. If so, it could have merit in treating fetal growth restriction. Preclinical studies, animal toxicology studies and clinical trials (non-pregnant population) have shown DM199 to be safe and well tolerated. DM199 is a protein meaning it is unlikely to cross the placenta and reach the fetus. These properties make DM199 an ideal candidate to evaluate as a possible treatment of preeclampsia and possibly fetal growth restriction. This protocol describes an unblinded study to determine an effective and safe dose of DM199 for women with preeclampsia and/or fetal growth restriction.
Type of trial Non-Randomised
Acronym (If the trial has an acronym then please provide) DM199
Disease(s) or condition(s) being studied Pregnancy and Childbirth
Sub-Disease(s) or condition(s) being studied
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/11/2024
Actual trial start date 13/11/2024
Anticipated date of last follow up 01/11/2026
Actual Last follow-up date
Anticipated target sample size (number of participants) 120
Actual target sample size (number of participants)
Recruitment status Recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Single Group Non-randomised Numbered containers Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group DM199 Part 1: Ascending dose finding study including up to 30 women with preeclampsia complicated by severe hypertension who need delivery within 72 hours. Three women will be recruited in each sequential cohort. Based on previous studies in non-pregnant individuals, significant blood pressure decreases are expected to occur when the dose is 1.5 µg/kg or higher. To be cautious, we will be starting with a dose that is 15 times lower than this (0.1 µg/kg). The dose escalation is presented in table 2 below. The highest dose is within the safety ranges and is within the FDA approved dose range. The FDA has approved a maximum SC dose of 15µg/kg for human administration, and we will not exceed this limit. The subcutaneous dose that is equivalent to the IV dose is six times higher. The first cohort will only receive an IV dose. If this is tolerated, we will repeat this low dose and add a SC dose. The SC dose is added as the half-life of the IV dose is short. Part 2: Safety and efficacy study with 30 women in each cohort using a dose from Part 1. The dose will be determined by Part 1 2.1: Women with preeclampsia with severe hypertension needing delivery with 72 hours 2.2: Women with preterm preeclampsia undergoing expectant management 2.3: Women with fetal growth restriction admitted for inpatient monitoring Until delivery N/A 120
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
A diagnosis of preeclampsia and/or fetal growth restriction Gestational age between 27 weeks 0 days and 42 weeks 0 days Viable singleton pregnancy Admitted for inpatient hospital management Viable singleton pregnancy Severe complications of preeclampsia which include eclampsia, pulmonary edema, HELLP syndrome, severe renal involvement, cerebrovascular event is defined as an ischaemic or haemorrhagic stroke associated with clinical symptoms and definitive signs on imaging and or a liver haematoma or rupture Placental abruption Clinical infection eg. chorioamnionitis Underlying maternal cardiac disease including a significant arrhythmia, a conduction abnormality or severe valvular disease or congenital or acquired heart disease Significant maternal vascular disease eg. renal artery stenosis Patient is unable, or unwilling to give consent, or is under the age of 18. Suspicion or diagnosis of a major fetal anomaly or malformation or chromosomal abnormality. A major fetal anomaly is defined as anomalies or malformations that create significant medical problems for the neonate or that require specific surgical or medical management. Established fetal compromise that necessitates urgent delivery History of clinically significant allergic reactions such as angioedema or anaphylaxis requiring hospitalization or familial angioedema Participant is currently participating in or has participated in a study using an investigational device or drug or received an investigational drug or investigational use of a licensed drug within 30 days prior to screening Women with an active malignancy Adult: 19 Year-44 Year 18 Year(s) 50 Year(s) Female
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
No 10/04/2024 Health Research Ethics Committee Stellenbosch University
Ethics Committee Address
Street address City Postal code Country
Francie van Zyl Drive, Tygerberg 7505 Cape Town 7505 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Part 1 Incidence of treatment adverse events Until 6 weeks after the due date
Primary Outcome Part 1 Umbilical cord blood levels of DM199 after birth Collected from the cord, after the birth of the baby
Primary Outcome Part 1 Acute change in maternal blood pressure from baseline Assessed immediately after the completion of the infusion, at 30 minutes post-infusion and at 24 hours after the intravenous dose
Secondary Outcome Part 1 Maternal pharmacokinetic profile of DM199 in preeclampsia Collected at multiple timepoints after drug administration
Secondary Outcome Part 1 Change in maternal blood pressure from baseline to delivery Baseline and delivery
Secondary Outcome Part 1 Uterine contractions From drug administration to delivery
Primary Outcome Part 2.1 Change in maternal blood pressure from baseline Assessed immediately after the completion of the infusion, at 30 minutes post-infusion and 24 hours after the initial dose
Primary Outcome Part 2.1 Incidence of treatment emergent events Until 6 weeks post partum
Primary Outcome Part 2.1 Umbilical cord blood levels of DM199 after birth Cord blood after delivery of the fetus
Secondary Outcome Part 2.1 Uterine contractions From administration of drug till delivery
Secondary Outcome Part 2.1 Episodes of severe hypertension or hypotension after administration of DM199 From administration of drug until delivery
Secondary Outcome Part 2.1 Use of other antihypertensive agents From administration of drug until delivery
Secondary Outcome Part 2.1 Changes in uterine and ophthalmic artery Doppler parameters From administration of drug until delivery
Primary Outcome Part 2.2 Prolongation of pregnancy From administration of drug until delivery
Primary Outcome Part 2.2 Change in 24-hour protein creatinine ratio one week after enrolment, compared to baseline values Enrollment and one week later
Primary Outcome Part 2.2 Need to increase or decrease other antihypertensive agents From enrollment until delivery
Primary Outcome Part 2.2 Incidence of treatment emergent adverse events From drug administration until 6 weeks after the due date
Primary Outcome Part 2.1 Umbilical cord blood levels of DM199 after birth Cord blood after delivery of the fetus
Secondary Outcome Part 2.2 Change in maternal blood pressure from baseline From administration of drug till delivery
Secondary Outcome Part 2.2 Number of women reaching 34 weeks gestation Delivery
Secondary Outcome Part 2.2 Severe hypertension or hypotension From drug administration to delivery
Secondary Outcome Part 2.2 Uterine contractions From drug administration till delivery
Secondary Outcome Part 2.2 Changes in uterine artery, ophthalmic artery and fetal Doppler flow indices From drug administration till delivery
Secondary Outcome Part 2.2 Neonatal length of stay at Tygerberg hospital and overall, in any hospital 6 weeks after the due date
Primary Outcome Part 2.3 Changes in uterine artery and ophthalmic artery Doppler flow indices From drug administration till delivery
Primary Outcome Part 2.3 Changes in fetal Doppler parameters From drug administration till delivery
Primary Outcome Part 2.3 Birthweight centile Delivery
Primary Outcome Part 2.3 Incidence of treatment emergent adverse events From drug administration until 6 weeks after the due date
Primary Outcome Part 2.3 Umbilical cord blood levels of DM199 after birth Cord blood after delivery of the fetus
Secondary Outcome Part 2.3 Prolongation of delivery Measured from time of first dose to delivery
Secondary Outcome Part 2.3 Fetal growth trajectory If two ultrasounds measuring fetal growth are done during the pregnancy
Secondary Outcome Changes in maternal blood pressure From drug administration to delivery
Secondary Outcome Part 2.3 Use of antihypertensive medication (if unmedicated at enrolment or the need to increase or decrease other antihypertensive agents From drug administration till delivery
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Department of Obstetrics and Gynaecology Tygerberg Hospital Stellenbosch University Francie van Zyl Drive Tygerberg Cape Town 7505 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
Diamedica 301 Carlson Parkway, Suite 210 Minneapolis MN 55305 United States of America
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Stellenbosch University Victoria Street Stellenbosch 7600 South Africa University
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Catherine Cluver cathycluver@hotmail.com +27823210298 Department of Obstetrics and Gynaecology, Faculty of Health Sciences, Stellenbosch University, Francie van Zyl Drive
City Postal code Country Position/Affiliation
Cape Town 7505 South Africa Professor
Role Name Email Phone Street address
Public Enquiries Catherine Cluver cathycluver@sun.ac.za +27823210298 Department of Obstetrics and Gynaecology, Faculty of Health Sciences, Stellenbosch University, Francie van Zyl Drive
City Postal code Country Position/Affiliation
Cape Town 7505 South Africa Professor
Role Name Email Phone Street address
Scientific Enquiries Catherine Cluver cathycluver@sun.ac.za +27823210298 Department of Obstetrics and Gynaecology, Faculty of Health Sciences, Stellenbosch University, Francie van Zyl Drive
City Postal code Country Position/Affiliation
Cape Town 7505 South Africa Professor
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes All of the individual participant data collected during the trial, after deidentification and after the results have been published. Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol After publication of the primary results Available on reasonable request to the principle investigator
URL Results Available Results Summary Result Posting Date First Journal Publication Date
www.preeclampsiaresearch.com No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Actual trial start date 13/11/2024 Trial started 13 Nov 2024
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Target no of participants 16/04/2024 Typing error There will be 30 women included in part 1 and 90 women in part 2. This is a total of 120 women. 180 120
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Recruitment status 13/11/2024 Recruitment started Not yet recruiting Recruiting
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 16/04/2024 Further details on number in each group have been added Experimental Group, DM 199, Part 1: Ascending dose finding study including up to 30 women with preeclampsia complicated by severe hypertension who need delivery within 72 hours. Three women will be recruited in each sequential cohort. Based on previous studies in non-pregnant individuals, significant blood pressure decreases are expected to occur when the dose is 1.5 µg/kg or higher. To be cautious, we will be starting with a dose that is 15 times lower than this (0.1 µg/kg). The dose escalation is presented in table 2 below. The highest dose is within the safety ranges and is within the FDA approved dose range. The FDA has approved a maximum SC dose of 15µg/kg for human administration, and we will not exceed this limit. The subcutaneous dose that is equivalent to the IV dose is six times higher. The first cohort will only receive an IV dose. If this is tolerated, we will repeat this low dose and add a SC dose. The SC dose is added as the half-life of the IV dose is short. Part 2: Safety and efficacy study with 30 women in each cohort using a dose from Part 1. The dose will be determined by Part 1 2.1: Women with preeclampsia with severe hypertension needing delivery with 72 hours 2.2: Women with preterm preeclampsia undergoing expectant management 2.3: Women with fetal growth restriction admitted for inpatient monitoring , Until delivery, N/A, 30,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 16/04/2024 A description has been added Experimental Group, DM 199, Part 1: Ascending dose finding study including up to 30 women with preeclampsia complicated by severe hypertension who need delivery within 72 hours. Three women will be recruited in each sequential cohort. Based on previous studies in non-pregnant individuals, significant blood pressure decreases are expected to occur when the dose is 1.5 µg/kg or higher. To be cautious, we will be starting with a dose that is 15 times lower than this (0.1 µg/kg). The dose escalation is presented in table 2 below. The highest dose is within the safety ranges and is within the FDA approved dose range. The FDA has approved a maximum SC dose of 15µg/kg for human administration, and we will not exceed this limit. The subcutaneous dose that is equivalent to the IV dose is six times higher. The first cohort will only receive an IV dose. If this is tolerated, we will repeat this low dose and add a SC dose. The SC dose is added as the half-life of the IV dose is short. Part 2: Safety and efficacy study with 30 women in each cohort using a dose from Part 1. The dose will be determined by Part 1 2.1: Women with preeclampsia with severe hypertension needing delivery with 72 hours 2.2: Women with preterm preeclampsia undergoing expectant management 2.3: Women with fetal growth restriction admitted for inpatient monitoring , Until delivery, N/A, 30, Experimental Group, Part 1, Part 1: Ascending dose finding study including up to 30 women with preeclampsia complicated by severe hypertension who need delivery within 72 hours. Three women will be recruited in each sequential cohort. Based on previous studies in non-pregnant individuals, significant blood pressure decreases are expected to occur when the dose is 1.5 µg/kg or higher. To be cautious, we will be starting with a dose that is 15 times lower than this (0.1 µg/kg). The dose escalation is presented in table 2 below. The highest dose is within the safety ranges and is within the FDA approved dose range. The FDA has approved a maximum SC dose of 15µg/kg for human administration, and we will not exceed this limit. The subcutaneous dose that is equivalent to the IV dose is six times higher. The first cohort will only receive an IV dose. If this is tolerated, we will repeat this low dose and add a SC dose. The SC dose is added as the half-life of the IV dose is short. Part 2: Safety and efficacy study with 30 women in each cohort using a dose from Part 1. The dose will be determined by Part 1 2.1: Women with preeclampsia with severe hypertension needing delivery with 72 hours 2.2: Women with preterm preeclampsia undergoing expectant management 2.3: Women with fetal growth restriction admitted for inpatient monitoring , Until delivery, N/A, 30,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 16/04/2024 More details added Experimental Group, Part 1, Part 1: Ascending dose finding study including up to 30 women with preeclampsia complicated by severe hypertension who need delivery within 72 hours. Three women will be recruited in each sequential cohort. Based on previous studies in non-pregnant individuals, significant blood pressure decreases are expected to occur when the dose is 1.5 µg/kg or higher. To be cautious, we will be starting with a dose that is 15 times lower than this (0.1 µg/kg). The dose escalation is presented in table 2 below. The highest dose is within the safety ranges and is within the FDA approved dose range. The FDA has approved a maximum SC dose of 15µg/kg for human administration, and we will not exceed this limit. The subcutaneous dose that is equivalent to the IV dose is six times higher. The first cohort will only receive an IV dose. If this is tolerated, we will repeat this low dose and add a SC dose. The SC dose is added as the half-life of the IV dose is short. Part 2: Safety and efficacy study with 30 women in each cohort using a dose from Part 1. The dose will be determined by Part 1 2.1: Women with preeclampsia with severe hypertension needing delivery with 72 hours 2.2: Women with preterm preeclampsia undergoing expectant management 2.3: Women with fetal growth restriction admitted for inpatient monitoring , Until delivery, N/A, 30, Experimental Group, Part 1 DM199, Part 1: Ascending dose finding study including up to 30 women with preeclampsia complicated by severe hypertension who need delivery within 72 hours. Three women will be recruited in each sequential cohort. Based on previous studies in non-pregnant individuals, significant blood pressure decreases are expected to occur when the dose is 1.5 µg/kg or higher. To be cautious, we will be starting with a dose that is 15 times lower than this (0.1 µg/kg). The dose escalation is presented in table 2 below. The highest dose is within the safety ranges and is within the FDA approved dose range. The FDA has approved a maximum SC dose of 15µg/kg for human administration, and we will not exceed this limit. The subcutaneous dose that is equivalent to the IV dose is six times higher. The first cohort will only receive an IV dose. If this is tolerated, we will repeat this low dose and add a SC dose. The SC dose is added as the half-life of the IV dose is short. Part 2: Safety and efficacy study with 30 women in each cohort using a dose from Part 1. The dose will be determined by Part 1 2.1: Women with preeclampsia with severe hypertension needing delivery with 72 hours 2.2: Women with preterm preeclampsia undergoing expectant management 2.3: Women with fetal growth restriction admitted for inpatient monitoring , Until delivery, N/A, 30,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 16/04/2024 The number in the group size has been changed to reflect the total number as requested by the PACTR registry. Experimental Group, Part 1 DM199, Part 1: Ascending dose finding study including up to 30 women with preeclampsia complicated by severe hypertension who need delivery within 72 hours. Three women will be recruited in each sequential cohort. Based on previous studies in non-pregnant individuals, significant blood pressure decreases are expected to occur when the dose is 1.5 µg/kg or higher. To be cautious, we will be starting with a dose that is 15 times lower than this (0.1 µg/kg). The dose escalation is presented in table 2 below. The highest dose is within the safety ranges and is within the FDA approved dose range. The FDA has approved a maximum SC dose of 15µg/kg for human administration, and we will not exceed this limit. The subcutaneous dose that is equivalent to the IV dose is six times higher. The first cohort will only receive an IV dose. If this is tolerated, we will repeat this low dose and add a SC dose. The SC dose is added as the half-life of the IV dose is short. Part 2: Safety and efficacy study with 30 women in each cohort using a dose from Part 1. The dose will be determined by Part 1 2.1: Women with preeclampsia with severe hypertension needing delivery with 72 hours 2.2: Women with preterm preeclampsia undergoing expectant management 2.3: Women with fetal growth restriction admitted for inpatient monitoring , Until delivery, N/A, 30, Experimental Group, DM199, Part 1: Ascending dose finding study including up to 30 women with preeclampsia complicated by severe hypertension who need delivery within 72 hours. Three women will be recruited in each sequential cohort. Based on previous studies in non-pregnant individuals, significant blood pressure decreases are expected to occur when the dose is 1.5 µg/kg or higher. To be cautious, we will be starting with a dose that is 15 times lower than this (0.1 µg/kg). The dose escalation is presented in table 2 below. The highest dose is within the safety ranges and is within the FDA approved dose range. The FDA has approved a maximum SC dose of 15µg/kg for human administration, and we will not exceed this limit. The subcutaneous dose that is equivalent to the IV dose is six times higher. The first cohort will only receive an IV dose. If this is tolerated, we will repeat this low dose and add a SC dose. The SC dose is added as the half-life of the IV dose is short. Part 2: Safety and efficacy study with 30 women in each cohort using a dose from Part 1. The dose will be determined by Part 1 2.1: Women with preeclampsia with severe hypertension needing delivery with 72 hours 2.2: Women with preterm preeclampsia undergoing expectant management 2.3: Women with fetal growth restriction admitted for inpatient monitoring , Until delivery, N/A, 120,
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 14/10/2024 Adding ethics approval letter FALSE, Health Research Ethics Committee Stellenbosch University, Francie van Zyl Drive, Tygerberg 7505, Cape Town, 7505, South Africa, 10 Apr 2024, , 0219389677, ethics@sun.ac.za, FALSE, Health Research Ethics Committee Stellenbosch University, Francie van Zyl Drive, Tygerberg 7505, Cape Town, 7505, South Africa, 10 Apr 2024, , 0219389677, ethics@sun.ac.za, 29416_28426_4737.pdf