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PI4 - 早産子癇前症における妊娠延長に対するメトホルミンの評価試験 (PI4)

2026年9月23日 更新者：Lina Bergman

子癇前症介入 4 - 早産子癇前症における妊娠延長に対するメトホルミンを評価する三重盲検第 III 相ランダム化対照試験

Preterm preeclampsia is a severe condition for both the mother and the fetus. Currently, the only treatment available to stop disease progression is termination/delivery of the fetus and placenta. Therefore, preterm preeclampsia carries the highest rates of neonatal morbidity and mortality due to iatrogenic preterm birth. There is evidence suggesting metformin, a drug commonly used to treat diabetes in and outside pregnancy, may be able to counter the pathophysiology of preeclampsia, raising the possibility that it could be used to treat the condition. This multi centre double blind randomised controlled trial aims to investigate if metformin can prolong gestation, lower neonatal length of stay and increase birthweight in a Nordic setting.

調査の概要

状態

募集

条件

介入・治療

詳細な説明

Preeclampsia is globally responsible for 60,000 maternal deaths per year, and far greater numbers of fetal losses. Preterm preeclampsia is a severe variant with the highest rates of neonatal morbidity and mortality due to iatrogenic preterm birth (clinicians are forced to deliver the baby preterm for maternal or fetal health reasons).

There is preclinical evidence suggesting metformin, a drug commonly used to treat diabetes in and outside pregnancy, may be able to counter the pathophysiology of preeclampsia, raising the possibility that it could be used to treat the condition.

Previous research from the Preeclampsia Intervention 2 trial (PI2) show that metformin was able to delay delivery in early preterm preeclampsia. Metformin extended release (ER) was associated with a median 7.6-day prolongation of pregnancy (geometric mean ratio (GMR) 1.39 (95% CI 0.99 to 1.96) P=0.057).Trends towards increased birthweight (mean difference 110gm (95%CI -80 to 300), a decreased length of stay at the neonatal intensive care unit (median difference 5.0 days less; GMR 0.86, 95% CI 0.62 to 1.2) and a shorter period of admission in any neonatal ward (median difference 12.0 days less; GMR 0.82, 95% CI 0.57 to 1.18) in the metformin ER group were found. Importantly, while gastrointestinal side effects were common, no serious adverse events related to trial medications were observed.

The PI 2 trial has shown that metformin may be a disease modifying treatment for preterm preeclampsia. The trial is being repeated in a larger scale in the PI3 trial in South Africa to also assess neonatal outcomes. In the Nordic countries, the demographics of the population are different and expectant management of preeclampsia allows for the women to reach 37 weeks of gestation as opposed to 34 weeks of gestation in the PI2 trial. This trial aims to investigate if metformin can prolong gestation, lower neonatal length of stay and increase birthweight in a Nordic setting. Follow up of mothers and children will be carried out two years post partum.

研究の種類

介入

入学 (推定)

294

段階

  • フェーズ 3

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究連絡先

研究連絡先のバックアップ

研究場所

  • スウェーデン
      • Borås、スウェーデン、50455
        • 募集
        • Södra Älvsborgs Hospital
        • コンタクト：
        • 主任研究者：
          • Lina Bergman, Associate Professor
      • Falun、スウェーデン、79129
      • Gothenburg、スウェーデン、416 85
      • Linköping、スウェーデン、581 85
      • Lund、スウェーデン、221 85
        • 募集
        • Skåne University Hospital
        • コンタクト：
        • コンタクト：
      • Malmö、スウェーデン、205 02
        • 募集
        • Skåne University Hospital
        • コンタクト：
      • Skövde、スウェーデン、549 49
        • 募集
        • Skaraborg Hospital
        • コンタクト：
      • Stockholm、スウェーデン、17176
        • 募集
        • Karolinska University Hospital Solna
        • コンタクト：
          • Anna Sandström, Associate Professor
          • 電話番号：0046-739829820
          • メール：anna.sandstrom@ki.se
        • コンタクト：
      • Stockholm、スウェーデン、182 88
        • 募集
        • Danderyd Hospital
        • コンタクト：
      • Stockholm、スウェーデン、14157
        • 募集
        • Karolinska University Hospital Huddinge
        • コンタクト：
          • Anna Sandström, Associate Professor
          • 電話番号：0046-739829820
          • メール：anna.sandstrom@ki.se
        • コンタクト：
      • Trollhättan、スウェーデン、461 74
        • 募集
        • Norra Älvsborgs County Hospital
        • 主任研究者：
          • Lina Bergman, Associate Professor
        • コンタクト：
      • Umeå、スウェーデン、901 85
        • 募集
        • Norrland´s University Hospital
        • コンタクト：
        • 主任研究者：
          • Marie-Therese Vinnars, PhD
      • Uppsala、スウェーデン、75237
        • 募集
        • Uppsala University Hospital
        • コンタクト：
      • Västerås、スウェーデン、72335
        • 募集
        • Västmanlands Hospital Västerås
        • コンタクト：
        • 主任研究者：
          • Linda Lindström, PhD
  • ノルウェー
      • Lørenskog、ノルウェー、N-1474
        • 募集
        • Akershus University Hospital
        • コンタクト：
        • 主任研究者：
          • Camilla Haavaldsen, PhD
      • Oslo、ノルウェー、0372
        • 募集
        • Oslo University Hospital
        • コンタクト：
          • Trond Michelsen, Professor
          • 電話番号：0047-23072619
          • メール：trmi1@ous-hf.no
        • 主任研究者：
          • Ingvil Krarup Sørbye, Professor
  • フィンランド
      • Helsinki、フィンランド、00290
        • 募集
        • Helsinki University Hospital
        • コンタクト：
        • 主任研究者：
          • Pia Villa, Associate Professor
      • Tampere、フィンランド、33520
        • 募集
        • Tampere University Hospital
        • コンタクト：
        • 主任研究者：
          • Hannele Laivuori, Professor

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

18年歳以上 (大人、高齢者)

健康ボランティアの受け入れ

いいえ

受講資格のある性別

女性

説明

Inclusion Criteria:

  • A diagnosis of preeclampsia (defined as hypertension in combination with significant proteinuria (albumin/creatinine ratio >8 mg/mmol, protein/creatinine ratio>30 mg/mmol or >2+ protein on a urinary dipstick) has been made by the attending clinician
  • The managing clinicians have made the assessment to proceed with expectant management.
  • The subject has given written consent to participate in the study.
  • The woman must be 18 years of age or older
  • The gestational age is between 22+0 weeks to 33+6 weeks with a viable fetus
  • The woman carries a singleton pregnancy

Exclusion Criteria:

  • Contraindications to treatment with metformin as outlined in SmPC
  • Contraindications for expectant management of preeclampsia such as an immediate indication for delivery according to SFOG guidelines for preeclampsia (https://www.sfog.se/media/338533/pe-riktlinje-230214.pdf).
  • Type 1 Diabetes Mellitus
  • Current use of metformin
  • Known or suspected allergies against metformin
  • Reluctance or language difficulties that result in difficulty understanding the meaning of study participation
  • Unable to understand the informed consent process
  • Previous participation in the study
  • Established fetal compromise that necessitates imminent delivery (including planned delivery after 48 hours of corticosteroid treatment). This will be decided by the clinical team before expectant management is offered to the patient.
  • Suspicion of a major known fetal anomaly or malformation.
  • Renal disease or dysfunction, suggested by a creatinine level greater than or equal to 125 µmol/L or rapidly declining renal function
  • Known acute or chronic metabolic acidosis, including diabetic ketoacidosis
  • Not suitable for inclusion by the opinion of the investigator

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか？

デザインの詳細

  • 主な目的：処理
  • 割り当て：ランダム化
  • 介入モデル：並列代入
  • マスキング：トリプル

武器と介入

参加者グループ / アーム
介入・治療
アクティブコンパレータ：Metformin ER

Metformin ER oral tablet 500 mg three times daily and increased to one gram (two tablets) three times daily as tolerated.
薬：Metformin ER

Metformin ER, one gram three times daily taken orally. Once the participants have been recruited, they will start by taking one 500 mg tablet three times a day. If well tolerated it will be increased day two to a maximum of two tablets three times a day. Treatment will continue until delivery. If there are side effects that are not tolerable, the dose will be decreased and the participant will remain blinded. Each participant will keep a treatment diary and number of tablets taken will be documented by the participant or hospital staff. The study will not alter or interfere with treatment or care routinely given for preterm preeclampsia.

他の名前：
  • グルコファージSR 500mg徐放錠
プラセボコンパレーター：Placebo

1 placebo tablet three times daily and increased to 2 placebo tablets three times daily as tolerated.
薬：Placebo

Placebo, two tablets three times daily taken orally. Once the participants have been recruited, they will start by taking one tablet three times a day. If well tolerated it will be increased day two to a maximum of two tablets three times a day. Treatment will continue until delivery. If there are side effects that are not tolerable, the dose will be decreased and the participant will remain blinded. Each participant will keep a treatment diary and number of tablets taken will be documented by the participant or hospital staff. The study will not alter or interfere with treatment or care routinely given for preterm preeclampsia.

この研究は何を測定していますか？

主要な結果の測定

結果測定
メジャーの説明
時間枠
Pregnancy prolongation
時間枠：From randomisation to delivery, measured in days and hours, up to 105 days

Length of pregnancy from diagnosis of preeclampsia to delivery
From randomisation to delivery, measured in days and hours, up to 105 days

二次結果の測定

結果測定
メジャーの説明
時間枠
Time for neonatal care
時間枠：From birth to discharge from neonatal care, measured in days and hours, up to 126 days

Time for neonatal care from birth to discharge
From birth to discharge from neonatal care, measured in days and hours, up to 126 days
Neonatal birth weight
時間枠：At birth

Birth wight measured in grams
At birth

その他の成果指標

結果測定
メジャーの説明
時間枠
Occurrence of maternal death
時間枠：Registered from inclusion to two month post partum

Occurrence of maternal death
Registered from inclusion to two month post partum
Occurrence of Eclampsia
時間枠：Registered from inclusion to two month post partum

Occurrence of Eclampsia
Registered from inclusion to two month post partum
Occurrence of Cerebral vascular event
時間枠：Registered from inclusion to two month post partum

Occurrence of Cerebral vascular event
Registered from inclusion to two month post partum
Occurrence of posterior reversible encephalopathy syndrome
時間枠：Registered from inclusion to two month post partum

Occurrence of posterior reversible encephalopathy syndrome
Registered from inclusion to two month post partum
Occurrence of pulmonary edema
時間枠：Registered from inclusion to two month post partum

Occurrence of pulmonary edema
Registered from inclusion to two month post partum
Occurrence of left ventricular failure
時間枠：Registered from inclusion to two month post partum

Occurrence of left ventricular failure
Registered from inclusion to two month post partum
Occurrence of renal dialysis
時間枠：Registered from inclusion to two month post partum

Occurrence of renal dialysis
Registered from inclusion to two month post partum
Occurrence of renal failure
時間枠：Registered from inclusion to two month post partum

Occurrence of renal failure:≥ 90 µmol/L or no urinary output for 6 hours
Registered from inclusion to two month post partum
Occurrence of elevated liver transaminases
時間枠：Registered from inclusion to two month post partum

Occurrence of elevated liver transaminases: ALT or AST ≥ 2 times highest normal value (ALAT >1.5 µkat/L and ASAT > 1.2 µkat/L)
Registered from inclusion to two month post partum
Occurrence of HELLP syndrome
時間枠：Registered from inclusion to two month post partum

Occurrence of HELLP (Haemolysis, elevated liver enzymes and low platelets) syndrome
Registered from inclusion to two month post partum
Occurrence of thrombocytopenia
時間枠：Registered from inclusion to two month post partum

Occurrence of thrombocytopenia (platelets <100 X 109/L)
Registered from inclusion to two month post partum
Occurrence of liver haematoma or rupture
時間枠：Registered from inclusion to two month post partum

Occurrence of liver haematoma or rupture
Registered from inclusion to two month post partum
Occurrence of admission to an intensive care unit
時間枠：Registered from inclusion to two month post partum

Occurrence of admission to an intensive care unit
Registered from inclusion to two month post partum
Occurrence of severe hypertension
時間枠：Registered from inclusion to two month post partum

Occurrence of severe hypertension (BP>160/110 mm Hg)
Registered from inclusion to two month post partum
Occurrence of disseminated intravascular coagulation
時間枠：Registered from inclusion to two month post partum

Occurrence of disseminated intravascular coagulation
Registered from inclusion to two month post partum
Occurrence of caesarean section
時間枠：At birth

Occurrence of caesarean section
At birth
Occurrence of major postpartum hemorrhage
時間枠：At birth

Occurrence of major postpartum hemorrhage (>1000 ml)
At birth
Occurrence of thromboembolic disease
時間枠：Registered from inclusion to two month post partum

Occurrence of thromboembolic disease: deep venous thrombosis or pulmonary embolism
Registered from inclusion to two month post partum
Duration of maternal postpartum hospital stay
時間枠：Registered from birth to hospital discharge

Duration of maternal postpartum hospital stay (days)
Registered from birth to hospital discharge
Number of antihypertensive drugs
時間枠：At discharge

Number of antihypertensive drugs at discharge after delivery
At discharge
Duration of antihypertensive medication
時間枠：From inclusion to two month postpartum

Duration of antihypertensive medication (days)
From inclusion to two month postpartum
Occurrence of intrauterine fetal demise
時間枠：From inclusion to birth

Occurrence of intrauterine fetal demise
From inclusion to birth
Occurrence of neonatal death
時間枠：From inclusion to two month post partum

Occurrence of neonatal death
From inclusion to two month post partum
Occurrence of growth restriction at birth
時間枠：At birth

Occurrence of growth restriction at birth (less than 2 standard deviations from median weight from Swedish birth weight growth curves).
At birth
Occurrence of grade 3 or 4 intraventricular hemorrhage
時間枠：Registered from birth to two month post partum

Occurrence of grade 3 or 4 intraventricular hemorrhage
Registered from birth to two month post partum
Occurrence of necrotizing enterocolitis
時間枠：Registered from birth to two month post partum

Occurrence of necrotizing enterocolitis
Registered from birth to two month post partum
Occurrence of reversed a-wave in the ductus venosus
時間枠：Registered from birth to two month post partum

Occurrence of reversed a-wave in the ductus venosus
Registered from birth to two month post partum
Occurrence of persistent reversed flow in the umbilical artery
時間枠：Registered from inclusion to birth

Occurrence of persistent reversed flow in the umbilical artery
Registered from inclusion to birth
Occurrence of redistribution in the middle cerebral artery
時間枠：Registered from birth to two month post partum

Occurrence of redistribution in the middle cerebral artery
Registered from birth to two month post partum
Occurrence of low APGAR score
時間枠：At birth

Occurrence of low APGAR score, defined as less than 4 at 5 minutes
At birth
Occurrence of umbilical artery pH below 7.1
時間枠：At birth

Occurrence of umbilical artery pH below 7.1
At birth
Occurrence of invasive ventilation, intubation and mechanical ventilation or non-invasive ventilatione outcome
時間枠：Registered from birth to two month post partum

Occurrence of invasive ventilation, intubation and mechanical ventilation or non-invasive ventilation; continuous positive airway pressure (CPAP) support or high flow nasal oxygen
Registered from birth to two month post partum
Occurrence of grade III/IV hyaline membrane disease
時間枠：Registered from birth to two month post partum

Occurrence of grade III/IV hyaline membrane disease
Registered from birth to two month post partum
Occurrence of surfactant use
時間枠：Registered from birth to two month post partum

Occurrence of surfactant use
Registered from birth to two month post partum
Occurrence of retinopathy of prematurity
時間枠：Registered from birth to two month post partum

Occurrence of retinopathy of prematurity
Registered from birth to two month post partum
Occurrence of neonatal sepsis
時間枠：Registered from birth to two month post partum

Occurrence of neonatal sepsis
Registered from birth to two month post partum
Tolerability and safety
時間枠：From inclusion to birth

Severity of nausea measured by PHASE-20 Severity of vomiting measured by PHASE-20 Severity of diarrhoea measured by PHASE-20 Severity of headache measured by PHASE-20
From inclusion to birth
Tolerability and safety
時間枠：From inclusion to birth

Occurrence of lactic acidosis (blood pH< 7.35 or blood lactate> 5 mM)
From inclusion to birth
Tolerability and safety
時間枠：From inclusion to birth

Drug adherence (measured by treatment diary)
From inclusion to birth
Pre-eclampsia-related biomarkers
時間枠：From inclusion to two years post partum

Concentrations of Soluble Fms-like tyrosine kinase-1 Concentrations of Placental growth factor Concentrations of Soluble endoglin
From inclusion to two years post partum
Gut and vaginal microbiome composition
時間枠：From inclusion to two years post partum

Omics-based analysis of the microbiome
From inclusion to two years post partum
Breastfeeding initiation
時間枠：From birth to two month postpartum

Breastfeeding initiation (measured by unvalidated breastfeeding questionnaire with no score)
From birth to two month postpartum
Depressive symptoms
時間枠：From inclusion to two years post partum

Depressive symptoms (measured by the Edinburgh Postnatal Depression Scale; 0-30, with higher scores indicating higher self-esteem)
From inclusion to two years post partum
Self-esteem
時間枠：From inclusion to two years post partum

Self-esteem (measured by The Rosenberg Self-Esteem Scale; 0-30, higher scores indicating higher self-esteem)
From inclusion to two years post partum
Perceived stress
時間枠：From inclusion to two years postpartum

Perceived stress (measured by the 10-item Perceived Stress Scale; 0-40, with higher scores indicating greater perceived stress)
From inclusion to two years postpartum
Breastfeeding self-efficacy
時間枠：From birth to two month postpartum

Breastfeeding self-efficacy (measured by the Breastfeeding Self-Efficacy Scale-Short Form; 14-70, higher score= greater breastfeeding self-efficacy)
From birth to two month postpartum
Health-related quality of life
時間枠：From inclusion to two years post partum

Health-related quality of life (measured using the EQ-5D-5L (the official name) and reported as the EQ-5D-5L index value and the EQ VAS [0-100]). EQ-5D-5L index values will be derived using country-specific value sets where available; higher index values indicate better health-related quality of life. The EQ VAS ranges from 0 to 100, with higher scores indicating better self-rated health)
From inclusion to two years post partum
Parental-infant bonding
時間枠：From birth to two month post partum

Parental-infant bonding (measured by the Postpartum Bonding Questionnaire; 0-125, higher score= greater impairment/difficulties in parent-infant bonding)
From birth to two month post partum
Health economic outcomes
時間枠：From birth to two years post partum

Cost-effectiveness short-term: direct healthcare costs (based on drug and healthcare use) for mother and child from enrolment until discharge, will be compared to incremental effects measured as prolongation of gestation

Cost-effectiveness long-term: societal costs (based on drug and healthcare use, and social insurance transactions) for mother and child from enrolment until two years postpartum, will be compared to incremental effects measured as prolongation of gestation and health-related quality of life
From birth to two years post partum
Risk of autism spectrum disorder
時間枠：At two years corrected age

Risk of autism spectrum disorder (evaluated by the Modified Checklist for Autism in Toddlers, Revised (M-CHAT/R); 20 questions resulting in score 0-20 where 0-2 indicates no risk, 3-7 moderate risk and 8-20 high risk for autism).
At two years corrected age
Cognitive development of the child
時間枠：At two years corrected age

Developmental screening (based on parental questionnaire Ages and Stages Questionnaire, Third Edition 24-months (ASQ-3);questions covering five key developmental domains; communication, gross motor, fine motor, problem-solving and personal-social skills; answers scored from 0-60 with age-specific cut-off levels at -2 and -1SD indicating clear or suspect developmental delay)
At two years corrected age
Cognitive development of the child
時間枠：At two years corrected age

Comprehensive developmental assessment (evaluated by the Bayley Scales of Infant Development-4 (BSID-4), with main scores for motor, language and cognitive function. Results expressed as age-corrected developmental scores in each domain with clear developmental delay at scores < 70 (-2SD) and suspect developmental delay at scores < 85 (-1SD).
At two years corrected age

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

スポンサー

Lina Bergman

協力者

The Swedish Research Council

捜査官

  • 主任研究者：Lina Bergman, Associate professor、Sahlgrenska University Hospital

出版物と役立つリンク

研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。

一般刊行物

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始 (実際)

2024年1月19日

一次修了 (推定)

2027年12月31日

研究の完了 (推定)

2029年12月31日

試験登録日

最初に提出

2023年8月28日

QC基準を満たした最初の提出物

2023年9月10日

最初の投稿 (実際)

2023年9月13日

学習記録の更新

投稿された最後の更新 (実際)

2026年9月28日

QC基準を満たした最後の更新が送信されました

2026年9月23日

最終確認日

2026年8月1日

詳しくは

本研究に関する用語

キーワード

追加の関連 MeSH 用語

その他の研究ID番号

  • EU Trial nr: 2022-502707-2-00

個々の参加者データ (IPD) の計画

個々の参加者データ (IPD) を共有する予定はありますか?

はい

IPD プランの説明

Metadata and statistical code will be published in public repositories upon release of the trial's primary results. Deidentified data may be shared upon reasonable request following a written application including a research proposal and ethical approval, in accordance with applicable ethical and legal requirements.

We plan to share data with similar ongoing or planned trials in South Africa and The Netherlands.

医薬品およびデバイス情報、研究文書

米国FDA規制医薬品の研究

いいえ

米国FDA規制機器製品の研究

いいえ

米国で製造され、米国から輸出された製品。

いいえ

この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。

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