The Evidence for Contraceptive Options and HIV Outcomes Trial (ECHO)

• ClinicalTrials.gov Identifier: NCT02550067
• Recruitment Status: Completed
• First Posted: September 15, 2015
• Last Update Posted: August 20, 2019
• Sponsor: FHI 360
• Collaborators: University of Washington; Wits Reproductive Health and HIV Institute; World Health Organization; Madibeng Centre for Research; Maternal Adolescent and Child Health Research; Qhakaza Mbokodo Research Clinic; The Aurum Institute NPC; Effective Care Research Unit; Emavundleni Research Centre; Setshaba Research Centre; University of North Carolina, Chapel Hill; Family Life Association of Swaziland; ICAP Columbia University; Kenya Medical Research Institute
• Information provided by (Responsible Party): FHI 360

Tracking Information

• First Submitted Date: September 12, 2015
• First Posted Date: September 15, 2015
• Last Update Posted Date: August 20, 2019
• Actual Study Start Date: December 14, 2015
• Actual Primary Completion Date: October 31, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 19, 2017)

Compare risks of HIV acquisition between women randomized to DMPA, LNG and copper IUD [ Time Frame: From enrollment to 18 months ]

HIV infection as measured by documented HIV seroconversion occurring post-enrolment

• Original Primary Outcome Measures (submitted: September 14, 2015): Compare risks of HIV acquisition between women randomized to DMPA, LNG and copper IUD [ Time Frame: From enrollment to 18 months ]

Current Secondary Outcome Measures (submitted: September 14, 2015)

• Compare pregnancy rates among women randomized to DMPA, LNG and copper IUD [ Time Frame: From enrollment to 18 months ]
• Compare rates of adverse events that lead to discontinuation among women randomized to DMPA, LNG and copper IUD [ Time Frame: From enrollment to 18 months ]
• Compare contraceptive continuation rates among women randomized to DMPA, LNG and copper IUD [ Time Frame: From enrollment to 18 months ]
• Compare SAEs among women randomized to DMPA, LNG and copper IUD [ Time Frame: From enrollment to 18 months ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Evidence for Contraceptive Options and HIV Outcomes Trial
• Official Title: A Multi Center, Open-Label, Randomised Clinical Trial Comparing HIV Incidence and Contraceptive Benefits in Women Using Depot Medroxyprogesterone Acetate (DMPA), Levonorgestrel (LNG) Implant, and Copper Intrauterine Devices (IUDs)
• Brief Summary: The ECHO Study is an open-label randomized clinical trial that will compare three highly effective, reversible methods of contraception (including a non-hormonal method) to evaluate whether there is a link between use of any of these methods and increased risk of acquiring HIV infection. A randomized clinical trial among about 7,800 women in four countries, ECHO will deliver evidence to support and guide individual, policy and programmatic decisions on contraception for women at risk of acquiring HIV infection.

Detailed Description

Approximately 7800 sexually active, HIV-negative women, 16-35 years old, seeking effective contraception, willing to be randomized to any of the study arms, and not desiring pregnancy for the duration of study participation will be randomly allocated to one of three study arms in a 1:1:1 ratio: depot medroxyprogesterone acetate (DMPA), levonorgestrel (LNG) implant, copper intrauterine device (IUD).

Enrollment will require an estimated 18 months and the total duration of the clinical portion of the study is estimated to be 36 months.

The primary objective is to compare the risks of HIV acquisition between women randomized to DMPA, levonorgestrel (LNG) implant, and copper IUDs. Secondary objectives are to compare: 1) pregnancy rates among women randomized to DMPA, LNG implant, and copper IUDs, 2) rates of serious adverse events among women randomized to DMPA, LNG implant, and copper IUDs, 3) rates of adverse events that lead to method discontinuation among women randomized to DMPA, LNG implant, and copper IUDs, and 4) contraceptive method continuation rates among women randomized to DMPA, LNG implant, and copper IUDs. Tertiary objectives are to evaluate: 1) whether age modifies the relationship between the three contraceptive methods and HIV acquisition, 2) whether HSV-2 status modifies the relationship between the three contraceptive methods and HIV acquisition, and 3) early HIV disease progression among sero-converters randomized to DMPA, LNG implant, and copper IUDs. Ancillary studies will assess biological mechanisms at the interface of contraceptives and markers of HIV risk.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Other

Condition

• HIV
• Contraception

Intervention

• Drug: DMPA
  Women randomized to DMPA, will receive an intramuscular injection of DMPA (medroxyprogesterone acetate sterile aqueous suspension 150 mg per 1 mL) at enrolment. Subsequent injections will be given every 3 months (i.e., at quarterly study visits) at the study site.
  Other Name: Depot medroxyprogesterone acetate
• Drug: LNG
  Women randomized to implants will receive LNG implants in the arm, at enrolment from trained clinicians.
  Other Name: Levonorgestrel implant
• Drug: Copper IUD
  Women randomized to IUDs will receive their IUDs at enrolment. Trained providers will insert T380a copper IUDs using standard insertion techniques.
  Other Name: Copper T380a IUD

Study Arms

• Active Comparator: Depot medroxyprogesterone acetate (DMPA)
  Women randomized to DMPA, will receive an intramuscular injection of DMPA (medroxyprogesterone acetate sterile aqueous suspension 150 mg per 1 mL) at enrolment. Subsequent injections will be given every 3 months (i.e., at quarterly study visits) at the study site.
  Intervention: Drug: DMPA
• Active Comparator: Levonorgestrel implant (LNG)
  Women randomized to implants will receive LNG implants in the arm, at enrolment from trained clinicians.
  Intervention: Drug: LNG
• Active Comparator: Copper T380a IUD
  Women randomized to IUDs will receive their IUDs at enrolment. Trained providers will insert T380a copper IUDs using standard insertion techniques.
  Intervention: Drug: Copper IUD

Publications *

• Beesham I, Mansoor LE, Joseph Davey DL, Palanee-Phillips T, Smit J, Ahmed K, Selepe P, Louw C, Singata-Madliki M, Kotze P, Heffron R, Parikh UM, Wiesner L, Rees H, Baeten JM, Beksinska M. Brief Report: Quantifiable Plasma Tenofovir Among South African Women Using Daily Oral Pre-exposure Prophylaxis During the ECHO Trial. J Acquir Immune Defic Syndr. 2022 Sep 1;91(1):26-30. doi: 10.1097/QAI.0000000000003023. Epub 2022 Jun 9.
• Ryan R, Mussa A, Singtaa-Madliki M, Batting J, Balakrishna Y, Morroni C, Hofmeyr GJ. Effects of Depot Medroxyprogesterone Acetate Intramuscular Injection, Copper Intrauterine Device and Levonorgestrel Implant Contraception on Estradiol Levels: An Ancillary Study of the ECHO Randomized Trial. Front Glob Womens Health. 2022 May 20;3:887541. doi: 10.3389/fgwh.2022.887541. eCollection 2022.
• Palanee-Phillips T, Rees HV, Heller KB, Ahmed K, Batting J, Beesham I, Heffron R, Justman J, Makkan H, Mastro TD, Morrison SA, Mugo N, Nair G, Kiarie J, Philip NM, Pleaner M, Reddy K, Selepe P, Steyn PS, Scoville CW, Smit J, Thomas KK, Donnell D, Baeten JM; ECHO Trial Consortium. High HIV incidence among young women in South Africa: Data from a large prospective study. PLoS One. 2022 Jun 3;17(6):e0269317. doi: 10.1371/journal.pone.0269317. eCollection 2022.
• Tanko RF, Bunjun R, Dabee S, Jaumdally SZ, Onono M, Nair G, Palanee-Phillips T, Harryparsad R, Happel AU, Gamieldien H, Qumbelo Y, Sinkala M, Scoville CW, Heller K, Baeten JM, Bosinger SE, Burgener A, Heffron R, Jaspan HB, Passmore JAS. The Effect of Contraception on Genital Cytokines in Women Randomized to Copper Intrauterine Device, Depot Medroxyprogesterone Acetate, or Levonorgestrel Implant. J Infect Dis. 2022 Sep 13;226(5):907-919. doi: 10.1093/infdis/jiac084.
• Mugo NR, Stalter RM, Heffron R, Rees H, Scoville CW, Morrison C, Kourtis AP, Bukusi E, Beksinka M, Philip NM, Beesham I, Deese J, Edward V, Donnell D, Baeten JM; Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. Incidence of Herpes Simplex Virus Type 2 Infection Among African Women Using Depot Medroxyprogesterone Acetate, a Copper Intrauterine Device, or a Levonorgestrel Implant for Contraception: A Nested Randomized Trial. Clin Infect Dis. 2022 Sep 10;75(4):586-595. doi: 10.1093/cid/ciab1027.
• Donnell D, Beesham I, Welch JD, Heffron R, Pleaner M, Kidoguchi L, Palanee-Phillips T, Ahmed K, Baron D, Bukusi EA, Louw C, Mastro TD, Smit J, Batting JR, Malahleha M, Bailey VC, Beksinska M, Rees H, Baeten JM; ECHO Trial Consortium. Incorporating oral PrEP into standard prevention services for South African women: a nested interrupted time-series study. Lancet HIV. 2021 Aug;8(8):e495-e501. doi: 10.1016/S2352-3018(21)00048-5. Epub 2021 Jun 11.
• Beksinska M, Issema R, Beesham I, Lalbahadur T, Thomas K, Morrison C, Hofmeyr GJ, Steyn PS, Mugo N, Palanee-Phillips T, Ahmed K, Nair G, Baeten JM, Smit J. Weight change among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: Findings from a randomised, multicentre, open-label trial. EClinicalMedicine. 2021 Apr 6;34:100800. doi: 10.1016/j.eclinm.2021.100800. eCollection 2021 Apr.
• Beesham I, Welch JD, Heffron R, Pleaner M, Kidoguchi L, Palanee-Phillips T, Ahmed K, Baron D, Bukusi EA, Louw C, Mastro TD, Smit J, Batting JR, Malahleha M, Bailey VC, Beksinska M, Donnell D, Baeten JM; ECHO Trial Consortium. Integrating oral PrEP delivery among African women in a large HIV endpoint-driven clinical trial. J Int AIDS Soc. 2020 May;23(5):e25491. doi: 10.1002/jia2.25491.
• Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium. HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial. Lancet. 2019 Jul 27;394(10195):303-313. doi: 10.1016/S0140-6736(19)31288-7. Epub 2019 Jun 13. Erratum In: Lancet. 2019 Jul 27;394(10195):302.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 7, 2017): 7830
• Original Estimated Enrollment (submitted: September 14, 2015): 7800
• Actual Study Completion Date: October 31, 2018
• Actual Primary Completion Date: October 31, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 16-35 years of age (previously pregnant 16 and 17 year olds, where permissible by national regulations and local IRB approval)
• HIV-seronegative
• Wants to use effective contraception
• Is able and willing to provide written informed consent
• Agrees to be randomized to either DMPA, LNG implant, or copper IUD
• Agrees to use assigned method for 18 months
• Agrees to follow all study requirements
• Intends to stay in the study area for the next 18 months, and willing and able to provide adequate locator information
• If has had a recent third trimester birth, is at least 6 weeks postpartum
• Is sexually active (has had vaginal sex within the last 3 months) or was pregnant within the last 3 months
• Agrees not to participate in studies of drugs or vaccines or any other clinical research study while participating in this study.

Exclusion Criteria:

• Reported medical contraindications (WHO MEC Category 3 or 4) to DMPA, LNG implant, or copper IUDs, including: recent septic abortion; suspicious unexplained vaginal bleeding; breast, cervical, uterine, or ovarian cancer; high BP or heart disease, venous thromboembolism, stroke, or diabetes; liver disease or liver tumours; use of liver enzyme inducing medications
• Is found to have pelvic tuberculosis or uterine fibroids with distortion of the uterine cavity on pelvic exam
• Has untreated mucus and purulent cervicitis on exam, untreated pelvic inflammatory disease (PID), or untreated known gonorrhea or chlamydia
• Has received a DMPA or NET-En injection in the last 6 months
• Has used an implant or an IUD in the last 6 months
• Is pregnant or intending to become pregnant in the next 18 months
• Has had a hysterectomy or sterilization
• Has previously participated in the study
• Has any condition (social or medical) which in the opinion of the investigator would make study participation unsafe or complicate data interpretation.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 16 Years to 35 Years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Kenya, South Africa, Swaziland, Zambia

Administrative Information

• NCT Number: NCT02550067
• Other Study ID Numbers: 523201
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Individual participant data that underlie the results reported in the primary analysis, after deidentification, are available beginning 3 months following article publication ending after 36 months. The study protocol is available upon publication.The statistical code is available 3 months after publication from the corresponding author. Data is available for researchers who provide a methodologically sound proposal, which will be reviewed by the ECHO Management Committee. Proposals should be directed to icrc@uw.edu; to gain access, data requestors will need to sign a data access agreement and any proposal will require approval by the ECHO Management Committee.
• Supporting Materials: Study Protocol
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: The data are available 3 months following publication of primary analysis, for 36 months.

• Current Responsible Party: FHI 360
• Original Responsible Party: Ward Cates, MD, FHI 360, Distinguished Scientist-President, Emeritus
• Current Study Sponsor: FHI 360
• Original Study Sponsor: Same as current

Collaborators

• University of Washington
• Wits Reproductive Health and HIV Institute
• World Health Organization
• Madibeng Centre for Research
• Maternal Adolescent and Child Health Research
• Qhakaza Mbokodo Research Clinic
• The Aurum Institute NPC
• Effective Care Research Unit
• Emavundleni Research Centre
• Setshaba Research Centre
• University of North Carolina, Chapel Hill
• Family Life Association of Swaziland
• ICAP Columbia University
• Kenya Medical Research Institute

• Investigators: Not Provided
• PRS Account: FHI 360
• Verification Date: August 2019