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| Name | Class |
|---|---|
| University of Cape Town | OTHER |
| City University of New York, School of Public Health | OTHER |
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This study will inform international medical guidelines as to whether the Levonorgestrel intrauterine device (LNG IUD), a highly effective long-acting reversible contraceptive method, is safe and acceptable as compared to the copper intrauterine device (C-IUD) for HIV-positive women in Cape Town, South Africa. If the LNG IUD is found to be safe and acceptable, the introduction of this method to HIV positive women in developing countries could significantly reduce unplanned pregnancy and mother-to-child transmission of HIV, and confer non-contraceptive benefits to HIV-positive women in Sub-Saharan Africa.
Design: Single site, double-blind, randomized controlled trial
Population: HIV-positive South African women between the ages of 18 and 40 years
Study size: At least 166 women
Study intervention: Levonorgestrel intrauterine device (LNG IUD) or the copper T-380 intrauterine device (C-IUD)
Duration & Follow-up: Approximately 48 months in total. Recruitment will take approximately 24 months. After enrollment, each participant will be followed for 24 months.
Primary Objectives: To compare LNG IUD safety to the safety of the C-IUD with respect to genital HIV shedding, a surrogate for potential for HIV transmission, overall and in the presence and absence of antiretroviral therapy (ART).
Secondary Objectives: 1) To compare LNG IUD safety to the safety of the C-IUD with respect to HIV progression as measured by changes in plasma viral load (VL) at 6 months between the two pre-ART study arms. 2) To explore LNG IUD safety with respect to non-HIV related outcomes, including hemoglobin change, incidence of sexually-transmitted infections (STIs) and pelvic inflammatory disease (PID). 3) To measure LNG IUD acceptability through device continuation and other measures for the LNG IUD as compared to the C-IUD. 4) To compare three genital tract sampling methods to determine which provides optimal recovery of HIV RNA and immune mediators over a series of three visits.
Primary Endpoints: Change in detection and quantity of HIV ribonucleic acid (RNA) genital VL measures between study arms at baseline and 6 months, and over 24 months following IUD insertion.
Secondary Endpoints: 1) Measures of HIV disease progression, including CD4 change, time to ART initiation, and mean plasma VL change from baseline to 6 and through 24 months among pre-ART women. 2) Hemoglobin change and incidence of STIs and PID for all participants through 24 months. 3) IUD continuation and expulsion rates between study arms comparing different IUDs over a 24-month period and acceptability measures through quantitative and qualitative methods. 4) Comparison of female genital tract sampling methods for recovery of HIV RNA as measured by VL and immune mediators (e.g. cytokines).
Study Site: Gugulethu Community Health Centre (GCHC), Cape Town, South Africa
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Copper T-380a Intrauterine Device (C-IUD) | Active Comparator | Copper T-380A Intrauterine Device with approximately 380 mm2 exposed copper. Devices used were those included as part of the South African public sector health formulary. |
|
| Levonorgestrel IUD (LNG-IUD) | Active Comparator | Levonorgestrel IUD containing 52 mg levonorgestrel registered for contraceptive use in South Africa at the time of the trial. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Mirena levonorgestrel IUD | Device | Intrauterine contraception system |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Participants With Detectable Genital Tract HIV Ribonucleic Acid (RNA) Viral Load (VL) | Number of women with detectable genital tract HIV RNA as measured with menstrual cup sampling at each scheduled visit. Level of detection was 20-40 copies/mL depending on assay; outcome was dichotomous with copies above level of detection coded as detectable and those below level of detection considered undetectable. | Enrollment to 24 months |
| Measure | Description | Time Frame |
|---|---|---|
| Participants With Detectable Plasma HIV Ribonucleic Acid (RNA) Viral Load Among Those Using Antiretroviral Therapy (ART) | The proportion of women using ART at enrollment with detectable plasma HIV RNA viral load. Viral load assays detected HIV RNA levels at 20-40 copies/mL as the lower limit of detection. The outcome measure coded values above that limit as detectable and those below as undetectable for women using ART and in mean viral load for women not using ART. |
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Inclusion Criteria
Willing and able to provide written informed consent (IC) to be screened for and to participate in the trial
Interested and willing to use the intrauterine device (IUD) as a family planning method.
Between 18 to 40 years of age (inclusive): This age range includes women during their years of greatest fertility and 18 is the age of majority for research consent in South Africa.
Willing to participate in all aspects of the study and to comply with study procedures and visits, for 24 months, including:
Has documented HIV infection
For pre-antiretroviral therapy (ART) entrants:
For ART-using entrants:
Intending residence in Cape Town area for next 30 months
No documented or known history of infertility or sterilization
No gross evidence of cervical neoplasia on examination
No prior history of ectopic pregnancy
No history of or suspected hormonally-dependent neoplasm or undiagnosed abnormal vaginal bleeding
Local language fluency and comprehension
Not participating in any other clinical trial with a biomedical intervention
Have no condition that, based on the opinion of the Site Principal Investigator (PI), would preclude provision of informed consent, make participation in the study unsafe, or complicate interpretation of data.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| B Landon Myer, MBChB, PhD | University of Cape Town | Principal Investigator |
| Catherine Todd, MD, MPH | FHI 360 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Cape Town | Cape Town | Western Cape | 7701 | South Africa |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 42245049 | Derived | Happel AU, Passmore JS, Sinkala M, Jaumdally SZ, Gamieldien H, Hu NC, Langwenya N, Jones HE, Hoover DR, Myer L, Todd CS. Genital Inflammatory Responses in Women Living with HIV Randomized to Copper or Levonorgestrel Intrauterine Contraceptives: A secondary analysis of a randomized trial. medRxiv [Preprint]. 2026 May 26:2026.05.24.26353969. doi: 10.64898/2026.05.24.26353969. | |
| 32611546 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Non-ART/LNG-IUD | Not eligible to use antiretroviral therapy at enrollment (ART) at enrollment/ randomized to and received the levonorgestrel 52 mg intrauterine device (LNG-IUD) |
| FG001 | Non-ART/C-IUD | Not eligible to use antiretroviral therapy (ART) at enrollment/ randomized to and received the copper T380-A intrauterine device (C-IUD) containing approximately 380 mm2 of exposed copper surface area |
| FG002 | ART Use at Enrollment/LNG-IUD | Using antiretroviral therapy (ART) and virally suppressed (plasma viral load<1000 copies/mL) at enrollment/ randomized to and received the levonorgestrel 52 mg intrauterine device (LNG-IUD) |
| FG003 | ART Use at Enrollment/C-IUD | Using antiretroviral therapy (ART) and virally suppressed (plasma viral load<1000 copies/mL) at enrollment/ randomized to and received the copper T380-A intrauterine device (C-IUD) containing approximately 380 mm2 of exposed copper surface area |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Women of reproductive age living with HIV
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| ID | Title | Description |
|---|---|---|
| BG000 | Non-ART/LNG-IUD | Not using ART at Enrollment (per national guidelines at study start, ART eligibility was initially limited to CD4<350 cells/mm3. This criteria was changed in 2015 to a threshold of CD4<500 cells/mm3 with an accompanying protocol amendment and then again in 2016 when ART initiation at diagnosis became standard of care, with a further protocol amendment. As such, there are relatively few participants in this arm.)/ LNG-IUD (the hormonal IUD used in this study is a T-shaped device containing 52mg levonorgestrel, releasing 20 mcg levonorgestrel daily.) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Participants With Detectable Genital Tract HIV Ribonucleic Acid (RNA) Viral Load (VL) | Number of women with detectable genital tract HIV RNA as measured with menstrual cup sampling at each scheduled visit. Level of detection was 20-40 copies/mL depending on assay; outcome was dichotomous with copies above level of detection coded as detectable and those below level of detection considered undetectable. | As-treated contributing any person-time at follow-up; proportions with detectable genital tract HIV RNA compared in longitudinal analysis. | Posted | Number | Participants | Enrollment to 24 months |
|
Participant follow-up time was up to 24 months; we followed unresolved adverse events a further 3-6 months until a final disposition was recorded.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Non-ART/LNG-IUD | Not using ART at Enrollment/LNG-IUD | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Depression | Psychiatric disorders | MedRA | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Amenorrhea | Blood and lymphatic system disorders | MedRA | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Catherine Todd | FHI 360 | +1-919-544-7040 | ctodd@fhi360.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 19, 2018 | Jan 5, 2022 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 28, 2016 | Jan 5, 2022 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D000163 | Acquired Immunodeficiency Syndrome |
| ID | Term |
|---|---|
| D015658 | HIV Infections |
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
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| Copper T-380a IUD |
| Device |
intrauterine contraception system |
|
| Enrollment to 24 months |
| Mean Hemoglobin Concentration as Part of Intrauterine Contraceptive Safety | Participant hemoglobin measured at baseline, 6, 12, 18, and 24 months with blood sample with mean hemoglobin calculated and trends over time assessed. Other safety measures were included with this secondary outcome, such as adverse events, summarized with descriptive statistics. | Enrollment to 24 months |
| Participants Continuing Use of the Allocated Intrauterine Device (IUD) | Measure of the number of women continuing to use the allocated intrauterine device (IUD) across all visits as a measure of acceptability. Proportion of women using the allocated IUD measured at each scheduled visit with time using the IUD adjusted for discontinuation at unscheduled visits. Continuation rate analyzed longitudinally with Kaplan-Meier survival analysis. | Enrollment to 24 months |
| HIV Ribonucleic Acid (RNA) Concentration by Lower Female Genital Tract Sampling Method | Proportion of specimens with quantifiable genital viral load compared by specific sampling method (menstrual cup, endocervical swab, and swab-enriched lavage) at enrollment, 3 months and 6 months among women not using antiretroviral therapy (ART). Allocated intrauterine device (IUD) was not considered in this analysis. | 6 months |
| Derived |
| Langwenya N, Todd CS, Jones HE, Hoover DR, Hu NC, Ronan A, Myer L. Risk-based screening to identify reproductive tract infection among HIV-infected women desiring use of intrauterine contraceptives. BMJ Sex Reprod Health. 2021 Apr;47(2):137-143. doi: 10.1136/bmjsrh-2019-200494. Epub 2020 Jul 1. |
| 32442189 | Derived | Todd CS, Jones HE, Langwenya N, Hoover DR, Chen PL, Petro G, Myer L. Safety and continued use of the levonorgestrel intrauterine system as compared with the copper intrauterine device among women living with HIV in South Africa: A randomized controlled trial. PLoS Med. 2020 May 22;17(5):e1003110. doi: 10.1371/journal.pmed.1003110. eCollection 2020 May. |
| Lost to Follow-up |
|
| Pregnancy |
|
| Withdrawal by Subject |
|
| Not eligible for 24 month visit |
|
| BG001 | Non-ART/C-IUD | Not using ART at Enrollment: (per national guidelines at study start, ART eligibility was initially limited to CD4<350 cells/mm3. This criteria was changed in 2015 to a threshold of CD4<500 cells/mm3 with an accompanying protocol amendment and then again in 2016 when ART initiation at diagnosis became standard of care, with a further protocol amendment. As such, there are relatively few participants in this arm.) /C-IUD (The copper IUD used in this study is the copper T Cu380A, containing 380 mm2 of exposed copper wire.) |
| BG002 | ART Use at Enrollment/LNG-IUD | Using ART at Enrollment (two new study arms were added in 2015 to include women using ART with clinical viral suppression (plasma viral load<1000 copies/mL) and change the primary outcome measure to detectable genital HIV RNA)/LNG-IUD (the hormonal IUD used in this study is a T-shaped device containing 52mg levonorgestrel, releasing 20 mcg levonorgestrel daily.) |
| BG003 | ART Use at Enrollment/C-IUD | Using ART at Enrollment (two new study arms were added in 2015 to include women using ART with clinical viral suppression (plasma viral load<1000 copies/mL) and change the primary outcome measure to detectable genital HIV RNA)/C-IUD (The copper IUD used in this study is the copper T Cu380A, containing 380 mm2 of exposed copper wire.) |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Recent (<=16 weeks) exposure to injectable progestin contraception | Count of Participants | Participants |
|
| OG001 | Non-ART/C-IUD | Not eligible to use antiretroviral therapy (ART) at enrollment/ randomized to and received the copper T380-A intrauterine device (C-IUD) containing approximately 380 mm2 of exposed copper surface area |
| OG002 | ART Use at Enrollment/LNG-IUD | Using antiretroviral therapy (ART) and virally suppressed (plasma viral load<1000 copies/mL) at enrollment/ randomized to and received the levonorgestrel 52 mg intrauterine device (LNG-IUD) |
| OG003 | ART Use at Enrollment/C-IUD | Using antiretroviral therapy (ART) and virally suppressed (plasma viral load<1000 copies/mL) at enrollment/ randomized to and received the copper T380-A intrauterine device (C-IUD) containing approximately 380 mm2 of exposed copper surface area |
|
|
|
| Secondary | Participants With Detectable Plasma HIV Ribonucleic Acid (RNA) Viral Load Among Those Using Antiretroviral Therapy (ART) | The proportion of women using ART at enrollment with detectable plasma HIV RNA viral load. Viral load assays detected HIV RNA levels at 20-40 copies/mL as the lower limit of detection. The outcome measure coded values above that limit as detectable and those below as undetectable for women using ART and in mean viral load for women not using ART. | Women recorded as using ART at a scheduled study visit with continued use of allocated intrauterine device. | Posted | Number | Participants | Enrollment to 24 months |
|
|
|
|
| Secondary | Mean Hemoglobin Concentration as Part of Intrauterine Contraceptive Safety | Participant hemoglobin measured at baseline, 6, 12, 18, and 24 months with blood sample with mean hemoglobin calculated and trends over time assessed. Other safety measures were included with this secondary outcome, such as adverse events, summarized with descriptive statistics. | Participants continuing use of the allocated intrauterine device (IUD) and having hemoglobin measured at 6-month intervals. | Posted | Mean | Standard Deviation | grams/deciliter | Enrollment to 24 months |
|
|
|
| Secondary | Participants Continuing Use of the Allocated Intrauterine Device (IUD) | Measure of the number of women continuing to use the allocated intrauterine device (IUD) across all visits as a measure of acceptability. Proportion of women using the allocated IUD measured at each scheduled visit with time using the IUD adjusted for discontinuation at unscheduled visits. Continuation rate analyzed longitudinally with Kaplan-Meier survival analysis. | Participants receiving the allocated IUD and contributing follow-up time at scheduled and unscheduled (e.g., request for IUD removal) visits. Analysis was proportion of women continuing their allocated IUD over time. The denominator at each scheduled visit changed based on number presenting or eligible (at 24 mos) for follow-up visits. | Posted | Number | Participants | Enrollment to 24 months |
|
|
|
|
| Secondary | HIV Ribonucleic Acid (RNA) Concentration by Lower Female Genital Tract Sampling Method | Proportion of specimens with quantifiable genital viral load compared by specific sampling method (menstrual cup, endocervical swab, and swab-enriched lavage) at enrollment, 3 months and 6 months among women not using antiretroviral therapy (ART). Allocated intrauterine device (IUD) was not considered in this analysis. | Women living with HIV who were not using ART receiving the allocated intrauterine device (IUD) had lower genital tract samples taken for genital tract viral load by three different methods: menstrual cup, endocervical swab, & swab-enriched lavage, at enrollment, 3-, and 6-month visits. Sampling order varied by visit (e.g., enrollment: menstrual cup, endocervical swab, endocervical swab-enriched lavage). The number in each group was different at enrollment, 3 months and 6 months. | Posted | Count of Participants | Participants | 6 months |
|
|
|
| 36 |
| 12 |
| 36 |
| 36 |
| 36 |
| EG001 | Non-ART/C-IUD | Not using ART at Enrollment//C-IUD | 0 | 31 | 12 | 31 | 31 | 31 |
| EG002 | ART Use at Enrollment/LNG-IUD | Using ART at Enrollment/LNG-IUD | 1 | 65 | 8 | 65 | 63 | 65 |
| EG003 | ART Use at Enrollment/C-IUD | Using ART at Enrollment/C-IUD | 1 | 67 | 7 | 67 | 65 | 67 |
| EG004 | All Women Using LNG-IUD | All women with equal to or more than one event using LNG-IUD | 1 | 101 | 20 | 101 | 99 | 101 |
| EG005 | All Women Using C-IUD | All women with equal to or more than one event using C-IUD | 1 | 98 | 19 | 98 | 96 | 98 |
| Low CD4 count | Immune system disorders | MedRA | Systematic Assessment | In keeping with the South Africa's 2015 guideline for initiation of ART based on CD4<=500, participant's CD4 count necessitated ART referral under new clinical guidelines. |
|
| Gallstones | Surgical and medical procedures | MedRA | Systematic Assessment |
|
| Pelvic Inflammatory Disease | Reproductive system and breast disorders | MedRA | Systematic Assessment |
|
| Pregnancy with IUD in place | Pregnancy, puerperium and perinatal conditions | MedRA | Systematic Assessment |
|
| Mood disorder | Psychiatric disorders | MedRA | Systematic Assessment |
|
| Hernia Surgery | Surgical and medical procedures | MedRA | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedRA | Systematic Assessment |
|
| Death - possibly injury | Injury, poisoning and procedural complications | MedRA | Systematic Assessment |
|
| Cellulitis | Infections and infestations | MedRA | Systematic Assessment |
|
| Liver failure/injury | Hepatobiliary disorders | MedRA | Systematic Assessment |
|
| Car accident- Broken Leg - Hospitalization | Injury, poisoning and procedural complications | MedRA | Systematic Assessment |
|
| Accident - Broken Leg - Hospitalization | Injury, poisoning and procedural complications | MedRA | Systematic Assessment |
|
| Abscess/Vagina Labia Majora | Reproductive system and breast disorders | MedRA | Systematic Assessment |
|
| Pulmonary Tuberculosis | Infections and infestations | MedRA | Systematic Assessment |
|
| Right Tubal Ectopic Pregnancy | Pregnancy, puerperium and perinatal conditions | MedRA | Systematic Assessment |
|
| Admission to psychiatric hospital | Psychiatric disorders | MedRA | Systematic Assessment |
|
| Stroke | Nervous system disorders | MedRA | Systematic Assessment |
|
| Cervical intraepithelial neoplasia | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedRA | Systematic Assessment |
|
| Death - unknown reasons | General disorders | MedRA | Systematic Assessment |
|
| IUD expulsion | Psychiatric disorders | MedRA | Systematic Assessment |
|
| Menorrhagia | Blood and lymphatic system disorders | MedRA | Systematic Assessment |
|
| Intermenstrual bleeding | Blood and lymphatic system disorders | MedRA | Systematic Assessment |
|
| Irregular/heavy uterine bleeding | Blood and lymphatic system disorders | MedRA | Systematic Assessment |
|
| Menstrual disorder | Blood and lymphatic system disorders | MedRA | Systematic Assessment |
|
| Pelvic pain | Reproductive system and breast disorders | MedRA | Systematic Assessment |
|
| Dysmenorrhea | Reproductive system and breast disorders | MedRA | Systematic Assessment |
|
| Enlarged Abdomen | Reproductive system and breast disorders | MedRA | Systematic Assessment |
|
| Breast Pain | Reproductive system and breast disorders | MedRA | Systematic Assessment |
|
| Lower back pain | Reproductive system and breast disorders | MedRA | Systematic Assessment |
|
| Leukorrhea | Infections and infestations | MedRA | Systematic Assessment |
|
| Cervicitis | Infections and infestations | MedRA | Systematic Assessment |
|
| Weight gain | General disorders | MedRA | Systematic Assessment |
|
| Weight loss | General disorders | MedRA | Systematic Assessment |
|
| Headache | General disorders | MedRA | Systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedRA | Systematic Assessment |
|
| Nausea | General disorders | MedRA | Systematic Assessment |
|
| Acne | Skin and subcutaneous tissue disorders | MedRA | Systematic Assessment |
|
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| D015229 |
| Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D012897 | Slow Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| Title | Measurements |
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| Title | Measurements |
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| Title | Measurements |
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| Title | Measurements |
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| 3 mos |
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| 6 mos |
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| 12 mos |
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| 18 mos |
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| 24 mos |
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| 6 months |
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| 12 months |
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| 18 months |
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| 24 months |
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| 3 mos |
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| 6 mos |
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| 12 mos |
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| 18 mos |
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| 24 mos |
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| 3 months |
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| 6 months |
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